β-Keto sulfones as inhibitors of 11β-hydroxysteroid dehydrogenase type I and the mechanism of action

Article abstract of DOI:10.1016/j.bmc.2007.04.035

The design, synthesis, and biological evaluation of β-keto sulfones as 11β-HSD1 inhibitors and the mechanism of inhibition are described here. This class of compounds is not active against 11β-HSD2 and therefore may have therapeutic potential for metabolic syndrome and type 2 diabetes.

Full text of DOI:10.1016/j.bmc.2007.04.035

Bioorganic & Medicinal Chemistry 15 (2007) 4396–4405
b-Keto sulfones as inhibitors of 11b-hydroxysteroid
dehydrogenase type I and the mechanism of action
Jason Xiang,a,* Manus Ipek,a Vipin Suri,b May Tam,b Yuzhe Xing,b Nelson Huang,a
Yanling Zhang,b James Tobin,b Tarek S. Mansoura and John McKewa
aChemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, MA 02140, USA
bCardiovascular and Metabolic Diseases, Wyeth Research, 200 Cambridge Park Drive, MA 02140, USA
Received 8 March 2007; revised 12 April 2007; accepted 18 April 2007
Available online 25 April 2007
Abstract—The design, synthesis, and biological evaluation of b-keto sulfones as 11b-HSD1 inhibitors and the mechanism of inhi-
bition are described here. This class of compounds is not active against 11b-HSD2 and therefore may have therapeutic potential for
metabolic syndrome and type 2 diabetes.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
itself is generated by the action of 11b-hydroxysteroid
dehydrogenase type 2 (11b-HSD2) on cortisol using
NAD as a cofactor (Fig. 1).6
Metabolic disorders, such as obesity and type 2 diabetes,
have assumed epidemic proportions and present major
challenges for healthcare systems.1–3 The dramatic in-
crease in the prevalence of obesity in recent years has
led to an increased recognition of ‘metabolic syndrome’,
a collection of metabolic and cardiovascular abnormal-
ities, that is a precursor to type 2 diabetes. Metabolic
syndrome is characterized by abdominal obesity, im-
paired glucose tolerance, dyslipidemia, low levels of high
density lipoprotein (HDL) cholesterol, and hyperten-
sion.4,5 Recent investigations have implicated aberrant
glucocorticoid receptor (GR) signaling in the develop-
ment of several phenotypes associated with metabolic
syndrome. Glucocorticoid hormones are key metabolic
regulators. The major activator of the GR in humans
is cortisol, and the adrenal cortex is the major source
of circulating cortisol. Recent evidence suggests that
GR signaling depends not only on the circulating corti-
sol levels, but also on the intracellular generation of cor-
tisol through reduction of the inactive glucocorticoid,
cortisone.6 The reduction reaction is catalyzed by 11b-
hydroxysteroid dehydrogenase type I (11b-HSD1) with
the concomitant oxidation of NADPH, while cortisone
These two enzymes have very different expression pro-
files: 11b-HSD1 is highest in liver, adipose, and the cen-
tral nervous system, whereas 11b-HSD2 is expressed in
kidney, colon and other tissues where mineralocorticoid
receptor (MR) signaling is important.6 The MR is acti-
vated by aldosterone but it can also bind cortisol with
similar affinity. 11b-HSD2 functions to reduce local cor-
tisol concentrations, thereby preventing illicit activation
of MR by cortisol. Disruption or mutations in the 11b-
HSD2 gene result in sodium retention, hypokalemia,
and hypertension because of inappropriate glucocorti-
coid occupation of the mineralocorticoid receptor in
the kidney.7
A potential role for 11b-HSD1 inhibitors in metabolic
disease in vivo has been demonstrated using a transgenic
OH
OH
O
OH
O
OH
HO
O
11β-HSD1
11β-HSD2
H
H
H
H
H
H
O
O
Keywords: HSD1; 11b-HSD1; Diabetes; Metabolic syndrome; Keto
sulfone; Synthesis.
cortisone
cortisol
*
Figure 1. Interconversion of cortisone and cortisol by 11b-HSD type 1
and 2 enzymes.
Corresponding author. Tel.:+1 617 665 5622; fax: +1 617 665 5682;
e-mail: jxiang@wyeth.com
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.04.035

J. Xiang et al. / Bioorg. Med. Chem. 15 (2007) 4396–4405
4397
mouse approach. Over-expression of 11b-HSD1 pre-
CF3
dominantly in adipose tissue shows several features sim-
ilar to those observed in patients with metabolic
syndrome.8a Transgenic mice over-expressing 11b-
HSD1 in the liver have also been generated and while
they are not obese they do show several features of met-
abolic syndrome.8b Inactivation of the 11b-HSD1 gene
in mice confers resistance to diet-induced obesity and
improves both insulin sensitivity and lipid profiles.8c
Administration of specific 11b-HSD1 inhibitors in
mouse models of insulin resistance led to improved
hyperglycemia and insulin sensitivity.9,10 Recent studies
with the non-specific 11b-HSD1 inhibitor carbenoxo-
lone also show improved hepatic insulin sensitivity and
decreased glucose production in humans.11 However,
the 11b-HSD2 inhibitory activity of carbenoxolone
was a limiting factor because it induces renal mineralo-
corticoid excess at higher doses.11 Thus, while inhibition
of 11b-HSD1 is an attractive strategy for the design of
therapeutics for metabolic syndrome and type 2 diabe-
tes, it is obvious that an inhibitor against 11b-HSD1
must not affect 11b-HSD2.
S
O
O
O
2a
Figure 3. b-Keto sulfone class of selective 11b-HSD1 inhibitors.
2. Chemistry
Preparation of b-keto sulfones was carried out through
the alkylation of sodium phenylsulfinate with bromom-
ethyl ketones.14 Using this one-step sequence and micro-
wave radiation, parallel synthetic libraries were quickly
prepared to explore the SAR around this lead. Analogs
2a–s were thus isolated in excellent yield (Scheme 1).
Variations to the keto portion of the molecules were
next explored. c-Keto sulfones were prepared through
the alkylation of sodium phenylsulfinate with chloroeth-
yl ketones 5a–d. This sequence again proceeded
smoothly under microwave heating condition at
100 ꢁC for 40 min. Final products 6a–d were isolated
in 70–85% yield after column chromatography (Scheme
2). Alternatively, 2a was reduced to b-hydroxy sulfone 7
with NaBH4. b-Oxime sulfone 8 was also prepared in
high yield by the condensation of b-keto sulfone 2b
and hydroxyamine in ethanol at 100 ꢁC for 20 min
(Scheme 3).15
Arylsulfonamidothiazole compounds from Biovitrum9
have been shown to be selective 11b-HSD1 inhibitors.
For example, BVT-14225 (Fig. 2) was reported to have
IC50 value of 52 nM against 11b-HSD1 in a microsomal
enzyme assay and to be 1000-fold less potent against
11b-HSD2. Since then, several publications related to
selective 11b-HSD1 inhibition have appeared.12 We
recently published our design, synthesis, and biological
evaluation of arylsulfonamidooxazoles as 11b-HSD1
inhibitors.13 In that paper, we also disclosed our seren-
dipitous discovery of a b-keto sulfone (Fig. 3, com-
pound 2a) as another class of potent 11b-HSD1
inhibitors.13 Presented herein is the synthesis and
detailed SAR study of b-keto sulfone series. Our screen-
ing approach was to use a cell-based assay to evaluate
analogs, this ensures that active compounds will also
be cell permeable and potentially more drug-like. Our
goal is to develop novel, selective, potent, orally bio-
available 11b-HSD1 inhibitors. This b-keto sulfone class
of compounds shows no activity against 11b-HSD2 at
concentration as high as 100 lM.
Acylsulfonamides 11a–e were obtained in almost quan-
titative yield by heating benzenesulfonamides with acet-
yl chlorides in acetonitrile (Scheme 4). Further
alkylation of the acylsulfonamides, nitrogen was carried
out with various alkylating agents in the presence of tri-
ethylamine to provide 11f and g (Schemes 5 and 6).
3. Results and discussion
Compound 2a was found to be a potent hit in the cell-
based assay and proved to be a good starting point for
further optimization (Table 1). It possessed a phenyl
O
NEt2
R1
a
O
S
O
O
O
N
N
O
SO2Na
+
R1
S
O
HN
S
N
H
O
Br
Cl
S
O
O
2a-s
3a-s
Sulfonamidoxazole 1
(Wyeth)
BVT-14225
(Biovitrum)
Scheme 1. Reagent and condition: (a) DMF, 120 ꢁC, thermal or
microwave irradiation.
O
H
N
N
N
NH
F
O
N
O
a
H
O
O
R2
S
R2
SO2Na
+
R3
O
Cl
Compound 544
(Merck)
Perhydroquinolylbenzamide
(Novartis)
R3
4
5a-d
6a-d
Figure 2. Examples of selective 11b-HSD1 inhibitors.
Scheme 2. Reagent and conditions: (a) DMF, 100 ꢁC, 40 min.

4398
J. Xiang et al. / Bioorg. Med. Chem. 15 (2007) 4396–4405
OH
O
O
N
HO
R1
b
O
S
O
Me
a
O
CF3
S
S
O
O
7
2a, R1=CF3
2b, R1=CH3
8
Scheme 3. Reagents and conditions: (a) NaBH4, THF/i-PrOH; (b) H2N–OH, ethanol, 100 ꢁC, 20 min.
O
a
R5
O
O
R4
S NH
O
R4
SO2NH2
9a-e
+
R5
Cl
11a-e
10a-e
b
O
O
R5
R4
S N
R6
O
11f-g
Scheme 4. Reagents and conditions: (a) pyridine, CH3CN, 25–100 ꢁC, 20–120 min; (b) Et3N, MeI, DMF, 100 ꢁC, 20–60 min.
Table 1. Biological activities of b-keto sulfones 2a–s and sulfonami-
dothiazole BVT-14225
OH
O
11β-HSD1
O
S
O
CF3
O
S
O
CF3
Compound R1
11b-HSD1 11b-HSD2
a a
IC50
(lM)
IC50
(lM)
2a
7
2a
2b
4-CF3–Ph
4-Me–Ph
0.187
0.102
0.075
0.09
0.2
>200
>200
>200
>200
>200
>200
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
>200
Scheme 5. b-Keto sulfone 2a a substrate of 11b-HSD1.
2c
2d
4-MeO–Ph
4-F–Ph
4-Cl–Ph
12
2e
2f
2g
3-MeO–Ph
3,4-DiCl–Ph
4-NO2–Ph
0.06
0.101
1.31
4.4
8
4
0
2h
2i
4-NEt2–Ph
2,4-DiMe–Ph
2,5-DiMeO–Ph
Benzhydryl
Et
2j
2k
1.2
9.3
2l
2m
2.9
15
90
2n
2o
t-Bu
C(CH3)2CH2CO2Et
3-Thienyl
0
10
20
30
40
5.0
TIME min
2p
2q
0.345
0.525
0.134
2-(3-Me)Benzothiophene
2-(5-Phenyl)thiophene
Scheme 6. Concentration of 2a versus incubation time.
2r
2s
BVT-14225
2-(2,4-DiCl-phenyl)-5-furan 0.169
1.5
ketone moiety with a strong electron-withdrawing group
CF3 at the para position. Variations at this para position
with methyl, fluoro, chloro (2b, 2d, 2e) maintained the
potency, while 2c with the electron-donating methoxy
showed improved potency. This suggested that both
electron-donating groups and electron-withdrawing
groups are well tolerated at this position. 3-Methoxy-
phenyl analog (2f) and 3,4-dichlorophenyl analog (2g)
are very potent indicating that both the para position
and the meta position can be functionalized further.
Analogs with polar groups such as nitro or amine de-
creased the activity dramatically. For example, diethyla-
mino substituted analog 2i was 23-fold less active than
the initial hit 2a.
a Assay run in duplicate.
this issue was to provide compounds with increased ste-
ric hindrance around the keto functionality. Analogs
with ortho-substitution at phenyl ring (2j, 2k) decreased
activity significantly. Bulky group such as benzhydryl
also decreased activity significantly (2l). Further SAR
study indicated aliphatic keto analogs (2m–o) all were
dramatically less potent. This suggested that the aro-
matic ring is a key part of the pharmacophore. In silico
modeling study of 2a shows that the benzene ring
achieves a strong p-stacking interaction with the en-
zyme’s active site residue tyrosine 177 side chain. The
modeling work and HSD1 crystal structure will be dis-
closed in due course. Potent inhibitors such as 2a–f were
The potential reactivity of keto moiety in these inhibi-
tors was a concern to us. The first approach to address

J. Xiang et al. / Bioorg. Med. Chem. 15 (2007) 4396–4405
4399
tested against 11b-HSD2 in an identical cell-based assay
O
S
OH
Ph
OH
O
O
N
O
O
Ph
and none were active at concentrations as high as
100 lM. This suggests that b-keto sulfones are 11b-
HSD1 specific inhibitors.
O
Ph
S
S
Ph
7
Cl
O
6
75 μM
8
Ph
24 μM
19 μM
The second approach to address potential ketone reac-
tivity was to investigate analogs with electron rich het-
erocycles conjugated to the ketone. Interestingly,
heteroaryl rings such as thienyl and furanyl (2p–s) serve
as potent phenyl bioisosteres.
O
O
O
S
O
O
S
O
O
Ph
O
Ph
S
N
H
Ph
Ph
Ph
Ph
2a
0.1 μM
20
NA
11a-e
> 100 μM
O
The third approach to decrease the electrophilicity of
keto moiety was to provide analogs with an extended
linker between keto and sulfone. c-Keto sulfones were
prepared in an effort to study this effect. All four c-keto
sulfones (6a–d) were weak inhibitors of 11b-HSD1 in
this cell-based assay (Table 2). Replacing the methylene
carbon linker with nitrogen led to the synthesis of acyl-
sulfonamides 11a–e. None of these analogs showed any
appreciable activity up to 100 lM (Table 3). Alkylation
with methyl and benzyl groups at nitrogen position led
to compounds 11f and 11g with increased lipophilicity.
Compounds 11g showed weak but improved activity
compared to analog 11a. The exact reason for this
improvement is not known. It is believed that the enzy-
matic site is large and quite lipophilic and tends to
prefer lipophilic groups. Removing acidic proton 11a
by alkylation forms more lipophilic compounds such
as 11f and 11g.
O
H
N
O
Ph
O
Ph
Ph
O
S
Ph
H
N
H
Ph
N
Ph
O
O
17
O
18
>100 μM
19
10 μM
0.1 μM
Figure 4. SAR of analogs with b-keto sulfone variations.
The mechanism by which these b-keto sulfones inhibit
11b-HSD1 activity was next examined. These studies
were especially interesting for the b-keto sulfone series
as the ketone functionality in these compounds could
mimic the role of the ketone moiety in the endogenous
11b-HSD1 substrate cortisone. Therefore b-keto sulfone
2a was incubated with 11b-HSD1 enzyme. Using LC/
MS with single ion monitoring (SIM) mode, the starting
compound concentration was found to decrease with the
incubation time. The half-life of 2a was found to be
16 min under these conditions. The study supports the
conclusion that b-keto sulfone 2a is substrate of 11b-
HSD1 enzyme. Compound 7, the product of enzymatic
reduction, is a very weak inhibitor of 11b-HSD1 with
IC50 over 100 lM.
To further confirm that the keto and sulfone moieties
were essential parts of pharmacophores, a few more
analogs were prepared for testing. Examples with varia-
tions around the keto moiety are b-hydroxy sulfone 7, b-
oxime sulfone 8, and b-amido sulfone 19. Examples with
variations around sulfone functionality are b-keto sul-
fonamides 17, b-keto amides 18, and 1,3-diketone 20.
Most of these analogs were weak inhibitors of 11b-
HSD1 (Fig. 4). The IC50 value of 1,3-diketone 20 was
not determined due to its cytotoxicity. However, b-keto
sulfonamide 17 did prove to be a potent 11b-HSD1
inhibitor and a detailed SAR for this template will be
disclosed in due course.
4. Conclusions
b-Keto sulfones were shown to be potent and selective
11b-HSD1 inhibitors. The most potent compound from
this series, 2f, has an IC50 value in cell-based assay of
60 nM and no activity in an analogous 11b-HSD2 assay
at 100 lM. Through a detailed SAR study, it was found
that both the keto and sulfone moieties are essential
parts of the pharmacophore. Replacement of either the
keto or sulfone functionality led to either decreased
activity or inactive compounds. A detailed enzymatic
study revealed that b-keto sulfones are the substrates
of 11b-HSD1 enzyme. They inhibit by competing with
substrate for the active site, they are then turned over
by the enzyme to products which are not inhibitors.
Table 2. Biological activities of c-keto sulfones 6a–d
a
Compound
R2
R3
11b-HSD1 IC50 (lM)
6a
6b
6c
6d
H
H
H
H
H
F
17.4
19.6
24
Cl
Br
25
a Assay run in duplicate.
Table 3. Biological activities of acylsulfonamides 11a–g
R4
R5
R6
11b-HSD1 IC50 (lM)
a
Compound
5. Experimental
11a
11b
11c
11d
11e
11f
11g
H
H
H
>100
>100
>100
>100
>100
35.5
All reagents and solvents were of commercial quality
and used without further purification. Column chroma-
tography was performed using Merck silica gel 60 (230–
400 mesh). Proton nuclear magnetic spectroscopy 1H
NMR spectra (400 MHz) were obtained on a Bruker
400 spectrometer. Chemical shifts are reported in parts
per million relative to Me4Si as internal standard.
H
3-Cl
4-CF3
H
H
H
H
4-Me
4-Cl
H
H
H
H
H
Me
Bn
H
H
5.7
a Assay run in duplicate.

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J. Xiang et al. / Bioorg. Med. Chem. 15 (2007) 4396–4405
Low-resolution mass spectra (MS) were obtained using
a Micromass Platform Electrospray Ionization Quadru-
pole mass spectrometer. High-resolution exact mass
measurements (HRMS) were performed on a Bruker
ApexIII 7T FT/ICR/MS. All intermediates were charac-
terized by 1H NMR. All new final SAR compounds
were determined to be consistent with proposed struc-
5.2.2. 1-(4-Methoxyphenyl)-2-(phenylsulfonyl)ethanone
(2c). Compound 2c was obtained as a light yellow solid
in 90% yield (0.416 g) according to general procedure 2.
Mp 114–116 ꢁC; 1H NMR (400 MHz, DMSO-d6) d ppm
3.85 (s, 3H), 5.24 (s, 2H), 7.03 (d, J = 8.84 Hz, 2H), 7.63
(t, J = 7.58 Hz, 2H), 7.73 (t, J = 7.45 Hz, 1H), 7.83–7.99
(m, 4H); HRMS: calcd for C15H14O4S + H +, 291.0686;
found (ESI-FTMS, [M+H]1+), 291.0687; HPLC Method
1: room temperature, 5.03 min, 99.61%. HPLC Method
2: room temperature, 5.10 min, 100.00%; Anal. Calcd
for C15H14O4S: C, 62.05; H, 4.86; N, 0. Found: C,
62.22; H, 4.83; N, <0.02.
1
ture by H NMR, MS, HRMS and were greater than
95% pure in two solvent systems (HPLC Method 1:
H2O–CH3CN and HPLC Method 2: H2O–MeOH) as
determined using an Agilent 1100 HPLC instrument
on a C18 column.
5.1. Preparation of b-keto sulfone (2a)
5.2.3. 1-(4-Fluorophenyl)-2-(phenylsulfonyl)ethanone (2d).
Compound 2d was obtained as a white solid in 92% yield
(0.596 g) according to general procedure 2. Mp 116–
118 ꢁC; 1H NMR (400 MHz, DMSO-d6) d ppm 5.34
(s, 2H), 7.31–7.40 (m, 2H), 7.63 (t, J = 7.58 Hz, 2H),
7.74 (t, J = 7.33 Hz, 1H), 7.90 (m, 2H), 8.05 (d,
J = 14.65 Hz, 1H), 8.05 (d, J = 3.54 Hz, 1H); HRMS:
calcd for C14H11FO3S + H +, 279.0486; found (ESI-
FTMS, [M+H]1+), 279.0486; HPLC Method 1: room
temperature, 5.10 min, 98.11%. HPLC Method 2: room
temperature, 5.16 min, 98.41%; Anal. Calcd for
C14H11FO3S: C, 60.42; H, 3.98; N, 0. Found: C, 60.31;
H, 3.85; N, <0.02.
To a solution of 2-bromo-1-(4-(trifluoromethyl)phenyl)-
ethanone (2.03 g, 7.59 mmol) in DMF (30 mL) was
added benzene sulfonic acid sodium salt (1.25 g,
7.59 mmol). The mixture was heated to 110 ꢁC for 2 h.
The mixture was cooled to room temperature and
DMF removed via rotavap. The residue thus obtained
was partitioned between EtOAc and water. Organic
layer was washed with brine, dried over MgSO4, and
concentrated under reduced pressure. After silica gel
column chromatography (20% EtOAc/hexane), 2a was
obtained as a white solid in 68% yield (1.70 g). Mp
104–106 ꢁC; 1H NMR (400 MHz, acetonitrile-d3) d
ppm 4.84 (s, 2H), 7.50 (t, J = 7.96 Hz, 2H), 7.62 (t,
J = 7.58, 7.56 Hz, 1H), 7.70 (d, J = 8.84 Hz, 2H), 7.78
(d, J = 7.32 Hz, 2H), 7.95 (d, J = 8.84 Hz, 2H); HRMS:
calcd for C15H11F3O3S + H +, 329.0454; found (ESI-
FTMS, [M+H]1+), 329.0454; HPLC Method 1: room
temperature, 5.76 min, 96.57%. HPLC Method 2: room
temperature, 6.28 min, 97.20%; Anal. Calcd for
C15H11F3O3S: C, 54.88; H, 3.38; N, 0. Found: C,
54.90; H, 3.22; N, <0.02.
5.2.4. 1-(4-Chlorophenyl)-2-(phenylsulfonyl)ethanone (2e).
Compound 2e was obtained as a white solid in 76% yield
(0.551 g) according to general procedure 2. Mp
133–135 ꢁC; 1H NMR (400 MHz, DMSO-d6) d ppm
5.33–5.36 (m, 2H), 7.61 (m, 4H), 7.73 (m, 1H), 7.89
(m, 2H) 7.97 (m, 2H); HRMS: calcd for
C14H11ClO3S + H +, 295.0190; found (ESI-FTMS,
[M+H]1+), 295.0194; HPLC Method 1: room tempera-
ture, 5.46 min, 99.34%. HPLC Method 2: room temper-
ature, 5.71 min, 99.38%; Anal. Calcd for C14H11ClO3S:
C, 57.05; H, 3.76; N, 0. Found: C, 57.06; H, 3.80; N,
<0.02.
5.2. General synthetic procedure 2 for compounds 2b–s
To a solution of bromoethylketone 3 (3.00 mmol) in
DMF (5 mL) was added benzene sulfonic acid sodium
salt (3.00 mmol). The reaction mixture was irradiated
under microwave condition at 120 ꢁC for 20 min. The
mixture was partitioned between CH2Cl2 and water. Or-
ganic phase was washed with brine, dried over MgSO4,
and concentrated under reduced pressure. The residue
was then subjected to column chromatography (10–
40% EtOAc/hexanes) to yield compounds 2b–s.
5.2.5. 1-(3-Methoxyphenyl)-2-(phenylsulfonyl)ethanone
(2f). Compound 2f was obtained as a yellow oil in
90% yield (0.164 g) according to general procedure 2.
Mp 96–98 ꢁC; H NMR (400 MHz, DMSO-d6) d ppm
3.81 (s, 3H), 5.37 (s, 2H), 7.24 (dd, J = 8.21, 2.65 Hz,
1H), 7.38–7.47 (m, 2H), 7.56 (d, J = 7.83 Hz, 1H), 7.63
(t, J = 7.58 Hz, 2H), 7.72 (d, J = 7.33 Hz, 1H), 7.90–
7.95 (m, 2H); HRMS: calcd for C15H14O4S + H +,
291.0686; found (ESI-FTMS, [M+H]1+), 291.0687;
HPLC Method 1: room temperature, 5.12 min,
98.51%. HPLC Method 2: room temperature,
5.22 min, 99.19%; Anal. Calcd for C15H14O4S: C,
62.05; H, 4.86; N, 0. Found: C, 62.22; H, 4.86; N, <0.02.
1
5.2.1. 2-(Phenylsulfonyl)-1-p-tolylethanone (2b). Com-
pound 2b was obtained according to the procedure de-
scribed in procedure 2 as a white solid in 85% yield
1
(1.50 g). Mp 124–126 ꢁC; H NMR (400 MHz, acetoni-
trile-d3) d ppm 2.53 (s, 3H), 4.92–5.02 (m, 2H), 7.44 (d,
J = 7.83 Hz, 2H), 7.72 (t, J = 7.71 Hz, 2H), 7.84 (t,
J = 7.58 Hz, 1H), 7.94 (d, J = 8.08 Hz, 2H), 8.01 (d,
J = 7.33 Hz, 2H); HRMS: calcd for C15H14O3S + H +,
275.0736; found (ESI-FTMS, [M+H]1+), 275.0728;
HPLC Method 1: room temperature, 5.28 min,
96.69%. HPLC Method 2: room temperature,
5.46 min, 97.83%; Anal. Calcd for C15H14O3S: C,
65.67; H, 5.14; N, 0. Found: C, 65.79; H, 5.18; N,
<0.02.
5.2.6. 1-(3,4-Dichlorophenyl)-2-(phenylsulfonyl)ethanone
(2g). Compound 2g was obtained as a white solid in
88% yield (0.625 g) according to general procedure 2.
Mp 149–151 ꢁC; 1H NMR (400 MHz, DMSO-d6) d
ppm 5.40 (s, 2H), 7.64 (t, J = 7.71 Hz, 2H), 7.74 (t,
J = 7.58, 7.33 Hz, 1H), 7.80 (d, J = 8.59 Hz, 1H), 7.87–
7.92 (m, 3H), 8.18 (d, J = 2.27 Hz, 1H); HRMS: calcd
for C14H10Cl2O3S + H +, 328.9800; found (ESI-FTMS,
[M+H]1+), 328.9804; HPLC Method 1: room tempera-

J. Xiang et al. / Bioorg. Med. Chem. 15 (2007) 4396–4405
4401
ture, 5.85 min, 99.61%. HPLC Method 2: room temper-
ature, 6.32 min, 99.71%.
NMR (400 MHz, DMSO-d6) d ppm 4.81 (s, 2H), 5.45
(s, 1H), 7.13 (d, J = 6.82 Hz, 4H), 7.19–7.37 (m, 6H),
7.63 (t, J = 7.71 Hz, 2H), 7.75 (t, J = 7.45 Hz, 1H),
5.2.7. 1-(4-Nitrophenyl)-2-(phenylsulfonyl)ethanone (2h).
Compound 2h was obtained as a yellow solid in 53%
yield (0.391 g) according to general procedure 2. Mp
137–139 ꢁC; 1H NMR (400 MHz, DMSO-d6) d ppm
5.47 (s, 2H), 7.65 (t, J = 7.71 Hz, 2H), 7.75 (t,
J = 7.45 Hz, 1H), 7.91 (d, J = 7.33 Hz, 2H), 8.19 (d,
J = 9.09 Hz, 2H), 8.32 (d, J = 8.84 Hz, 2H); HRMS:
calcd for C14H11NO5S þ NH4þ, 323.0696; found (ESI-
FTMS, [M+NH4]1+), 323.0694; HPLC Method 1: room
temperature, 5.17 min, 97.49%. HPLC Method 2: room
temperature, 5.20 min, 97.73%; Anal. Calcd for
C14H11NO5S: C, 55.08; H, 3.63; N, 4.59. Found: C,
55.28; H, 3.62; N, 4.46.
7.86 (d, J = 7.33 Hz, 2H); HRMS: calcd for
þ
C21H18O3S þ NH4
,
368.1315; found (ESI-FTMS,
[M + NH4]1+), 368.1317; HPLC Method 1: room tem-
perature, 5.67 min, 92.59%. HPLC Method 2: room
temperature, 6.50 min, 90.29%.
5.2.12. 1-(Phenylsulfonyl)butan-2-one (2m). Compound
2m was obtained as a white solid in 65% yield (0.338 g)
according to general procedure 2. Mp 43–46 ꢁC; 1H
NMR (400 MHz, DMSO-d6)
d
ppm 0.87 (t,
J = 7.07 Hz, 3H), 2.56 (q, J = 7.33 Hz, 2H), 4.69 (s, 2H),
7.66 (t, J = 7.83 Hz, 2H), 7.76 (t, J = 7.33, 7.32 Hz, 1H),
7.89 (d, J = 7.33 Hz, 2H); HRMS: calcd for
C10H12O3S + H +, 213.0580; found (ESI-FTMS,
[M+H]1+), 213.0583; HPLC Method 1: room tempera-
ture, 4.24 min, 100.00%. HPLC Method 2: room temper-
ature, 3.82 min, 100.00%; Anal. Calcd for C10H12O3S: C,
56.58; H, 5.70; N, 0. Found: C, 56.66; H, 5.52; N, <0.02.
5.2.8. 1-(4-(Diethylamino)phenyl)-2-(phenylsulfonyl)etha-
none (2i). Compound 2i was obtained as a light yellow
solid in 53% yield (0.426 g) according to general proce-
1
dure 2. Mp 104–105 ꢁC; H NMR (400 MHz, DMSO-
d6)
d ppm 1.11 (t, J = 6.95 Hz, 6H), 3.43 (q,
J = 7.07 Hz, 4H), 5.04 (s, 2H), 6.65 (d, J = 9.35 Hz,
2H), 7.62 (t, J = 7.71 Hz, 2H), 7.69–7.73 (m, 1H), 7.75
(d, J = 9.09 Hz, 2H), 7.88 (d, J = 7.33 Hz, 2H); HRMS:
calcd for C18H21NO3S + H +, 332.1315; found (ESI-
FTMS, [M+H]1+), 332.1321; HPLC Method 1: room
temperature, 5.60 min, 100.00%. HPLC Method 2:
room temperature, 5.89 min, 100.00%; Anal. Calcd for
C18H21NO3S: C, 65.23; H, 6.39; N, 4.23. Found: C,
65.41; H, 6.19; N, 4.19.
5.2.13. 3,3-Dimethyl-1-(phenylsulfonyl)butan-2-one (2n).
Compound 2n was obtained as a white solid in 85% yield
1
(0.413 g) according to general procedure 2. H NMR
(400 MHz, DMSO-d6) d ppm 1.00 (s, 9H), 4.94 (s,
2H), 7.64 (t, J = 7.58 Hz, 2H), 7.73 (t, J = 7.33 Hz,
1H), 7.87–7.94 (m, 2H); HRMS: calcd for
C12H16O3S + H +, 241.0893; found (ESI-FTMS,
[M+H]1+), 241.0894; HPLC Method 1: room tempera-
ture, 5.03 min, 99.61%. HPLC Method 2: room temper-
ature, 5.10 min, 100.00%.
5.2.9. 1-(3,5-Dimethylphenyl)-2-(phenylsulfonyl)ethanone
(2j). Compound 2j was obtained as a white solid in 95%
yield (0.504 g) according to general procedure 2. Mp
106–108 ꢁC; 1H NMR (400 MHz, DMSO-d6) d ppm
2.28 (s, 3H), 2.31 (s, 3H), 5.21 (s, 2H), 7.04–7.12 (m,
2H), 7.61 (t, J = 7.71 Hz, 2H), 7.72 (t, J = 7.33 Hz,
1H), 7.76 (d, J = 7.83 Hz, 1H), 7.85 (d, J = 7.33 Hz,
2H); HRMS: calcd for C16H16O3S + H +, 289.0893;
found (ESI-FTMS, [M+H]1+), 289.0897; HPLC Method
1: room temperature, 5.60 min, 99.52%. HPLC Method
2: room temperature, 5.92 min, 100.00%; Anal. Calcd
for C16H16O3S: C, 66.64; H, 5.59; N, 0. Found: C,
66.83; H, 5.54; N, <0.02.
5.2.14. Ethyl 3,3-dimethyl-4-oxo-5-(phenylsulfonyl)pent-
anoate (2o). Compound 2o was obtained as a white solid
in 65% yield (0.494 g) according to general procedure 2.
1H NMR (400 MHz, DMSO-d6) d ppm 1.05 (s, 6H),
1.10 (t, J = 7.33, 7.07 Hz, 3H), 2.58 (s, 2H), 3.96 (q,
J = 7.16 Hz, 2H), 4.91 (s, 2H), 7.63 (t, J = 7.58 Hz,
2H), 7.73 (t, J = 6.82 Hz, 1H), 7.92 (d, J = 7.07 Hz,
2H); HRMS: calcd for C15H20O5S + H +, 313.1104;
found (ESI-FTMS, [M+H]1+), 313.1107; HPLC Method
1: room temperature, 5.12 min, 100.00%. HPLC
Method 2: room temperature, 5.23 min, 100.00%.
5.2.15. 2-(Phenylsulfonyl)-1-(thiophen-3-yl)ethanone (2p).
Compound 2p was obtained as a light yellow solid in
62% yield (0.405 g) according to general procedure 1.
Mp 126–128 ꢁC; 1H NMR (400 MHz, DMSO-d6) d
ppm 5.19 (s, 2H), 7.46 (dd, J = 5.05, 1.26 Hz, 1H),
7.59–7.67 (m, 3H), 7.69–7.77 (m, 1H), 7.87–7.92 (m,
2H), 8.64 (dd, J = 2.78, 1.26 Hz, 1H); HRMS: calcd
for C12H10O3S2 + H +, 267.0144; found (ESI-FTMS,
[M+H]1+), 267.0144; HPLC Method 1: room tempera-
ture, 4.79 min, 99.38%. HPLC Method 2: room temper-
ature, 4.98 min, 99.49%; Anal. Calcd for C12H10O3S2: C,
54.12; H, 3.78; N, 0. Found: C, 54.08; H, 3.75; N, <0.02.
5.2.10. 1-(2,5-Dimethoxyphenyl)-2-(phenylsulfonyl)etha-
none (2k). Compound 2k was obtained as a white solid
in 64% yield (0.500 g) according to general procedure 2.
Mp 100–102 ꢁC; 1H NMR (400 MHz, DMSO-d6) d ppm
3.72 (s, 3H), 3.77 (s, 3H), 5.19 (s, 2H), 7.00 (d,
J = 3.28 Hz, 1H), 7.04 (d, J = 9.09 Hz, 1H), 7.11–7.18
(m, 1H), 7.60 (t, J = 7.58 Hz, 2H), 7.71 (t, J = 7.45 Hz,
1H), 7.85 (d, J = 7.33 Hz, 2H); HRMS: calcd for
C16H16O5S + H +, 321.0791; found (ESI-FTMS,
[M+H]1+), 321.0792; HPLC Method 1: room tempera-
ture, 5.16 min, 100.00%. HPLC Method 2: room temper-
ature, 5.33 min, 100.00%; Anal. Calcd for C16H16O5S: C,
59.99; H, 5.03; N, 0. Found: C, 59.92; H, 4.82; N, <0.02.
5.2.16. 1-(3-Methylbenzo[b]thiophen-2-yl)-2-(phenylsulfo-
nyl)ethanone (2q). Compound 2q was obtained as a light
yellow solid in 60% yield (0.161 g) according to general
procedure 1. Mp 158–159 ꢁC; 1H NMR (400 MHz,
DMSO-d6) d ppm 2.70 (s, 3H), 5.26 (s, 2H), 7.51
5.2.11. 1,1-Diphenyl-3-(phenylsulfonyl)propan-2-one (2l).
Compound 2l was obtained as a colorless oil in 63%
yield (0.534 g) according to general procedure 2. 1H

4402
J. Xiang et al. / Bioorg. Med. Chem. 15 (2007) 4396–4405
(t, J = 7.07 Hz, 1H), 7.59 (t, J = 7.07 Hz, 1H), 7.65 (t,
J = 7.58 Hz, 2H), 7.74 (d, J = 7.58 Hz, 1H), 7.93–7.98
(m, 2H), 8.02–8.07 (m, 2H); HRMS: calcd for
C17H14O3S2 + H +, 331.0457; found (ESI-FTMS,
[M+H]1+), 331.0454; HPLC Method 1: room tempera-
ture, 5.93 min, 97.20%. HPLC Method 2: room temper-
ature, 6.53 min, 97.35%.
131–133 ꢁC; 1H NMR (400 MHz, DMSO-d6) d ppm
3.40 (t, J = 7.20 Hz, 2H), 3.67 (t, J = 7.07 Hz, 2H),
7.34 (t, J = 8.97 Hz, 2H), 7.62–7.70 (m, 2H), 7.72–7.80
(m, 1H), 7.92–7.98 (m, 2H), 7.98–8.06 (m, 2H); HRMS:
calcd for C15H13FO3S + H +, 293.0642; found (ESI-
FTMS, [M+H]1+), 293.0643; HPLC Method 1: room
temperature, 5.33 min, 96.71%. HPLC Method 2: room
temperature, 5.88 min, 97.44%; Anal. Calcd for
C15H13FO3S: C, 61.63; H, 4.48; N, 0. Found: C, 61.40;
H, 4.60; N, <0.02.
5.2.17. 2-(Phenylsulfonyl)-1-(5-phenylthiophen-2-yl)etha-
none (2r). Compound 2r was obtained as a light pink so-
lid in 65% yield (0.432 g) according to general procedure
1
1. Mp 172–174 ꢁC; H NMR (400 MHz, DMSO-d6) d
5.3.3. 1-(4-Chlorophenyl)-3-(phenylsulfonyl)propan-1-one
(6c). Compound 6c was obtained as a white solid in
58% yield (0.530 g) according to general procedure 2.
1H NMR (400 MHz, DMSO-d6) d ppm 3.18 (t,
J = 7.20 Hz, 2H), 3.44 (t, J = 7.07 Hz, 2H), 7.33–7.39
(m, 2H), 7.40–7.47 (m, 2H), 7.51–7.57 (m, 1H), 7.68–
7.75 (m, 4H); HRMS: calcd for C15H13ClO3S + H +,
309.0348; found (ESI-FTMS, [M+H]1+), 309.0344;
HPLC Method 1: room temperature, 5.69 min,
95.13%. HPLC Method 2: room temperature,
6.36 min, 95.59%.
ppm 5.27 (s, 2H), 7.38–7.53 (m, 3H), 7.58–7.83 (m,
6H), 7.92–7.99 (m, 2H), 8.13 (d, J = 4.04 Hz, 1H);
HRMS: calcd for C18H14O3S2 + H +, 343.0457; found
(ESI-FTMS, [M+H]1+), 343.0452; HPLC Method 1:
room temperature, 5.95 min, 100.00%. HPLC Method
2: room temperature, 6.46 min, 100.00%; Anal. Calcd
for C18H14O3S2: C, 63.14; H, 4.12; N, 0. Found: C,
62.90; H, 3.92; N, <0.02.
5.2.18. 1-(5-(2,4-Dichlorophenyl)furan-2-yl)-2-(phenylsulfo-
nyl)ethanone (2s). Compound 2s was obtained as a
light yellow solid in 8% yield (0.019 g) according to
5.3.4. 1-(4-Bromophenyl)-3-(phenylsulfonyl)propan-1-one
(6d). Compound 6d was obtained as a white solid in
46% yield (0.456 g) according to general procedure 2.
Mp 152–154 ꢁC; 1H NMR (400 MHz, DMSO-d6) d
ppm 3.62 (t, J = 7.07 Hz, 2H), 3.89 (t, J = 7.07 Hz,
2H), 7.84–7.92 (m, 2H), 7.93–8.02 (m, 3H), 8.06–8.12
(m, 2H), 8.14–8.20 (m, 2H); HRMS: calcd for
C15H13BrO3S + H +, 352.9841; found (ESI-FTMS,
[M+H]1+), 352.9841; HPLC Method 1: room tempera-
ture, 5.79 min, 99.39%. HPLC Method 2: room temper-
ature, 6.46 min, 99.37%; Anal. Calcd for C15H13BrO3S:
C, 51.00; H, 3.71; N, 0. Found: C, 50.86; H, 3.47; N,
<0.02.
1
general procedure 2. H NMR (400 MHz, DMSO-d6)
d ppm 5.14 (s, 2H), 7.35 (d, J = 3.79 Hz, 1H),
7.62 (t, J = 8.21 Hz, 3H), 7.71 (t, J = 7.45 Hz, 1H),
7.78 (d, J = 3.79 Hz, 1H), 7.82 (d, J = 2.02 Hz, 1H),
7.91 (t, J = 7.96 Hz, 3H); HRMS: calcd for
C18H12Cl2O4S + H +, 394.9906; found (ESI-FTMS,
[M+H]1+), 394.9908; HPLC Method 1: room tempera-
ture, 6.42 min, 100%. HPLC Method 2: room tempera-
ture, 7.04 min, 100%.
5.3. General synthetic procedures for c-keto sulfones (6a–d)
To a solution of chloroethylketone 5 (2.97 mmol) in
DMF (5 mL) was added benzene sulfonic acid sodium
salt (2.96 mmol). The reaction mixture was irradiated
under microwave condition at 100 ꢁC for 30 min. The
mixture was cooled to room temperature and poured
into cold water. After stirring for 10 min, solid thus pre-
cipitated was collected by filtration, washed with water
three times, and then air-dried overnight. Purification
was done via silica gel column chromatography
(EtOAC/hexanes) to yield 6.
5.4. Synthesis of 2-(phenylsulfonyl)-1-(4-(trifluorometh-
yl)phenyl)ethanol (7)
To a solution of 2-(phenylsulfonyl)-1-(4-(trifluorometh-
yl)phenyl)ethanone (0.120 g, 0.67 mmol) in THF
(10 mL) and isopropanol (1 mL) was added NaBH4
(0.028 g, 0.134 mmol). After stirring for 1 h the reaction
mixture was quenched with NH4Cl (aq), partitioned be-
tween EtOAc/H2O, organic layer dried over MgSO4,
concentrated under reduced pressure, and purified via
column chromatography (5–30% EtOAC/hexanes).
Compound 7 was isolated as a white solid in 25% yield
(28 mg). Mp 97–98 ꢁC; 1H NMR (400 MHz, chloro-
form-d) d ppm 3.29–3.53 (m, 2H), 3.84 (d, J = 2.27 Hz,
1H), 5.38 (d, J = 9.85 Hz, 1H), 7.44 (d, J = 8.08 Hz,
5.3.1. 1-Phenyl-3-(phenylsulfonyl)propan-1-one (6a). Com-
pound 6a was obtained as an off-white solid in 69% yield
(0.562 g) according to general procedure 3. Mp 98–
100 ꢁC; 1H NMR (400 MHz, DMSO-d6) d ppm 3.41
(t, J = 7.07 Hz, 2H), 3.68 (t, J = 7.20 Hz, 2H), 7.49–
7.57 (m, 2H), 7.61–7.70 (m, 3H), 7.72–7.80 (m, 1H),
7.89–7.98 (m, 4H); HRMS: calcd for C15H14O3S + H +,
275.0736; found (ESI-FTMS, [M+H]1+), 275.0736;
HPLC Method 1: room temperature, 5.22 min, 99.63%.
HPLC Method 2: room temperature, 5.70 min,
99.67%; Anal. Calcd for C15H14O3S: C, 65.67;
H, 5.14; N, 0. Found: C, 65.57; H, 5.06; N, <0.02.
2H), 7.56–7.65 (m, 4H), 7.67–7.76 (m, 1H), 7.92–8.01
þ
(m, 2H); HRMS: calcd for C15H13F3O3S þ NH4
,
348.0876; found (ESI-FTMS, [M + NH4]1+), 348.0871;
HPLC Method 1: room temperature, 3.07 min, 99.5%.
5.5. Synthesis of (E)-2-(phenylsulfonyl)-1-p-tolylethanone
oxime (8)
5.3.2. 1-(4-Fluorophenyl)-3-(phenylsulfonyl)propan-1-one
(6b). Compound 6b was obtained as a white solid in 60%
yield (0.516 g) according to general procedure 3. Mp
To a solution of 2-(phenylsulfonyl)-1-p-tolylethanone
(0.150 g, 0.55 mmol) in ethanol (3 mL) was added
hydroxylamine HCl salt (0.076 g, 1.09 mmol). The

J. Xiang et al. / Bioorg. Med. Chem. 15 (2007) 4396–4405
4403
mixture was irradiated under microwave condition at
100 ꢁC for 40 min. The mixture was cooled to room tem-
perature and solvent removed by rotavap. The residue
was dissolved in methanol and purified via column chro-
matography (5–20% EtOAC/hexanes). Compound 8
reduced pressure, and purified via column chromatogra-
phy (3% MeOH/CH2Cl2) to give 11c as a white solid in
5% yield (0.039 g). Mp 365–370 ꢁC; 1H NMR
(400 MHz, DMSO-d6) d ppm 7.43 (s, 3H), 7.69 (d,
J = 7.07 Hz, 2H), 7.85 (d, J = 6.32 Hz, 2H), 8.07 (d,
J = 6.82 Hz, 2H); HRMS: calcd for C14H10F3NO3S +
H +, 330.0406; found (ESI-FTMS, [M+H]1+), 330.0421;
HPLC Method 1: room temperature, 6.15 min, 100.00%.
HPLC Method 2: room temperature, 5.48 min, 100.00%.
1
was isolated as a white solid in 37% yield (0.108 g). H
NMR (400 MHz, DMSO-d6) d ppm 2.31 (s, 3H), 4.90
(s, 2H), 7.15 (d, J = 8.08 Hz, 2H), 7.46–7.64 (m, 4H),
7.62–7.84 (m, 3H), 11.64 (s, 1H); HRMS: calcd for
C15H15NO3S + H +, 290.0845; found (ESI-FTMS,
[M+H]1+), 290.0844; HPLC Method 1: room tempera-
ture, 5.10 min, 97.95%. HPLC Method 2: room temper-
ature, 5.75 min, 98.06%.
5.6.4. N-[(4-Methylphenyl)sulfonyl]benzamide (11d).
Compound 11d was obtained as a off-white solid in
78% yield using procedures similar to those described
1
for 11a. H NMR (400 MHz, DMSO-d6) d ppm 2.40
5.6. Synthesis of acylsulfonamides (11a–e)
(s, 3H), 7.35–7.54 (m, 4H), 7.56–7.68 (m, 1H), 7.78–
7.94 (m, 4H), 12.48 (s, 1H); HRMS: calcd for
C14H13NO3S + H +, 276.0689; found (ESI-FTMS,
[M+H]1+), 276.0691; HPLC Method 1: room tempera-
ture, 5.09 min, 100.00%. HPLC Method 2: room tem-
perature, 5.74 min, 100.00%.
5.6.1. N-(Phenylsulfonyl)benzamide (11a). A solution of
benzene sulfonamide (1.6 g, 10.2 mmol) in CH3CN
(50 mL) was cooled to 0 ꢁC then added with benzoyl
chloride (1.43 g, 10.2 mmol) and Et3N (1.52 g,
15.0 mmol). Then the cooling bath was removed and
the reaction mixture was allowed to stir at ambient tem-
perature for 2 h. After CH3CN removal, the residue was
subjected to aqueous work up (CH2Cl2/H2O). Then
organic layer was dried over MgSO4, concentrated
under reduced pressure, and purified via column
chromatography (20–80% EtOAC/hexanes) to give 11a
as a white solid in 9% yield (0.23 g). Decomposed at
5.6.5. N-(4-Chlorophenylsulfonyl)benzamide (11e). Com-
pound 11e was obtained as a white solid in 75% yield
using procedures similar to those described for 11a. H
1
NMR (400 MHz, DMSO-d6)
d
ppm 7.50 (t,
J = 7.83 Hz, 2H), 7.60–7.67 (m, 1H), 7.70–7.77 (m,
2H), 7.84–7.89 (m, 2H), 7.98–8.05 (m, 2H), 12.66 (s,
1H); HRMS: calcd for C13H10ClNO3S + H +,
296.0143; found (ESI-FTMS, [M+H]1+), 296.0143;
HPLC Method 1: room temperature, 5.33 min,
98.96%. HPLC Method 2: room temperature,
6.04 min, 100.00%.
1
300 ꢁC; H NMR (400 MHz, MeOD) d ppm 7.40 (dd,
J = 4.55, 2.53 Hz, 2H), 7.44–7.66 (m, 4H), 7.93 (s, 2H),
8.06 (d, J = 6.06 Hz, 2H); HRMS: calcd for
C13H11NO3S + H +, 262.0532; found (ESI-FTMS,
[M+H]1+), 262.0538; HPLC Method 1: room tempera-
ture, 4.76 min, 100.00%. HPLC Method 2: room tem-
perature, 5.17 min, 100.00%.
5.7. Synthesis of N-alkylated b-keto sulfones (11f and g)
5.7.1. N-Methyl-N-(phenylsulfonyl)benzamide (11f). N-
(Phenylsulfonyl)benzamide (0.301 g, 1.15 mmol), iodo-
methane (0.489 g, 3.45 mmol), triethylamine (0.349 g,
3.49 mmol), and DMF (1 mL) were charged to a micro-
wave vial under argon. The reaction mixture was sub-
jected to microwave irradiation at 100 ꢁC for 40 min.
Then more iodomethane (2.27 g, 16.00 mmol) was added
and the reaction was repeated for an additional 20 min.
The reaction mixture was quenched with water and ex-
tracted with EtOAc. Organic layer was washed with satu-
rated sodium chloride, dried over MgSO4, and
concentrated under reduced pressure. The crude product
thus obtained was purified via column chromatography
(20% EtOAC/hexanes). Compound 11f was obtained as
a white solid in 22% yield (0.07 g). 1H NMR (400 MHz,
DMSO-d6) d ppm 3.31 (s, 3H), 7.48–7.56 (m, 2H), 7.58–
7.66 (m, 3H), 7.71 (t, J = 7.58 Hz, 2H), 7.81 (t,
J = 6.82 Hz, 1H), 8.03 (dd, J = 8.46, 1.39 Hz, 2H);
HRMS: calcd for C14H13NO3S + H +, 276.0689; found
(ESI-FTMS, [M+H]1+), 276.0682; HPLC Method 1:
room temperature, 5.41 min, 99.56%. HPLC Method 2:
room temperature, 5.83 min, 100.00%; Anal. Calcd for
C14H13NO3S: C, 61.07; H, 4.76; N, 5.09. Found: C,
61.05; H, 4.54; N, 5.05.
5.6.2. 3-Chloro-N-(phenylsulfonyl)benzamide (11b). A
solution of benzene sulfonamide (0.501 g, 3.19 mmol)
in DMF (5 mL) was added with 3-chlorobenzoyl
chloride (0.558 g, 3.19 mmol) and Et3N (0.376 g,
3.72 mmol). Then the reaction mixture was irradiated
under microwave at 60 ꢁC for 20 min, then at 100 ꢁC
for another 20 min. The reaction mixture was filtered
off through silica gel plug. Liquid phase was diluted with
CH3CN and purified via HPLC to give 11b as a white
1
solid in 14% yield (0.131 g). Mp 140–143 ꢁC; H NMR
(400 MHz, DMSO-d6) d ppm 7.52 (t, J = 7.83 Hz, 1H),
7.59–7.76 (m, 4H), 7.78–7.85 (m, 1H), 7.93 (t,
J = 1.77 Hz, 1H), 7.98–8.04 (m, 2H); HRMS: calcd for
C13H10ClNO3S ꢀ H +, 293.9997; found (ESI-FTMS,
[MꢀH]1ꢀ), 293.9991; HPLC Method 1: room tempera-
ture, 5.27 min, 100.00%. HPLC Method 2: room tem-
perature, 5.48 min, 100.00%.
5.6.3. N-(Phenylsulfonyl)-4-(trifluoromethyl)benzamide
(11c). A solution of benzene sulfonamide (0.570 g,
3.63 mmol) in acetonitrile (3.5 mL) was added with 4-
trifluoromethylbenzoyl chloride (0.946 g, 4.54 mmol)
and pyridine (1.43 g, 18.2 mmol). Then the reaction mix-
ture was irradiated at 75 ꢁC for 20 min. After CH3CN
removal, the residue was subjected to aqueous work
up (EtOAc/H2O), (EtOAc/saturated NaCl). Then or-
ganic layer was dried over MgSO4, concentrated under
5.7.2. N-Benzyl-N-(phenylsulfonyl)benzamide (11g). N-
(Phenylsulfonyl)benzamide (0.3 g, 1.15 mmol) and
benzyl bromide (0.589 g, 3.45 mmol), triethylamine

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J. Xiang et al. / Bioorg. Med. Chem. 15 (2007) 4396–4405
(0.349 g, 3.49 mmol) and DMF (1 mL) were charged to
a microwave vial under argon. The reaction mixture was
subjected to microwave irradiation at 100 ꢁC for 20 min.
The reaction mixture was quenched with water and
extracted with EtOAc. Organic layer was washed with
saturated sodium chloride, dried over MgSO4, and con-
centrated under reduced pressure. The crude product
thus obtained was purified via column chromatography
(20% EtOAC/hexanes) and trituration with hexanes.
Compound 11g was obtained as a white solid in 38%
5.9. Enzymatic study of compound 2a
Ten micromolars compound was incubated with 0.7 lM
purified 11b-HSD1 enzyme at room temperature in TBS
buffer (50 mM Tris, 150 mM NaCl) pH 7.4, containing
0.01% Tween-20. Cofactor of NADPH was at concen-
tration of 400 lM. One hundred microliters reaction
sample was quenched by three volumes of acetonitrile
at different incubation time (0, 10, 20, 40 min). After a
brief centrifugation at 12,000 rpm, the supernatant was
air-dried and reconstituted to 200 lL distilled water.
SIM was used to monitor the apparent molecular weight
for the b-keto sulfone compound. The half-life of the
compound is calculated from the integration change of
the SIM peak. LC/MS analysis was carried out with
an Agilent 1100 LC/MSD. The HPLC gradient went
from 98% water and 2% acetonitrile with 0.1% formic
acid to 100% acetonitrile with 0.1% formic acid in
10 min. The HPLC column was Thermo Aquasil C18
(2· 50 mm). Flow rate was 0.8 mL/min. Mass spectro-
metric detection was made using single ion monitoring
(SIM). The SIM was set to m/z 328 (M+H+).
1
yield (0.153 g). H NMR (400 MHz, DMSO-d6) d ppm
4.82 (s, 2H), 6.92–6.99 (m, 2H), 7.04–7.13 (m, 3H),
7.19–7.27 (m, 4H), 7.31–7.38 (m, 1H), 7.39–7.46 (m,
2H), 7.51–7.59 (m, 1H), 7.62–7.67 (m, 2H); HRMS:
calcd for C20H17NO3S + H +, 352.1002; found (ESI-
FTMS, [M+H]1+), 352.0989; HPLC Method 1: room
temperature, 6.29 min, 100.00%. HPLC Method 2:
room temperature, 6.86 min, 100.00%.
5.8. Determination of IC50 values in cell-based assay
CHO cells were stably transformed with plasmid con-
taining the full-length sequence of human 11b-HSD1
(Locuslink id. 3290) to generate the CHO–HSD1 cell
line. CHO cells were stably transformed with plasmid
containing the full-length sequence of human 11b-
HSD2 (Locuslink id. 3291) to generate the CHO–
HSD2 cell line.
Acknowledgments
We thank Dr. Xin Xu for coordinating and obtaining
metabolic stability data and pharmacokinetics data,
and Drs. Eddine Saiah and Steve Tam for editing the
manuscript.
Non-transformed CHO cells do not have detectable
11b-HSD1 or 11b-HSD2 activity. Cell-based assays
for 11b-HSD1 were performed using the CHO–
HSD1 cell line. The effect of test article on 11b-
HSD1 activity was assayed by determination of the
conversion of radioactive cortisone to cortisol. In this
assay, 50,000 CHO–HSD1 cells were plated in 24-well
plates and incubated overnight. The cells were washed
once with ethylene glycol dimethyl ether and 197.5 lL
ethylene glycol dimethyl ether was added to each well.
2.5 lL of the appropriate drug concentrations was
added to each well and the cells were incubated for
30 min at 37 ꢁC/5% CO2. [1,2-3H]-Cortisone was di-
luted to a concentration of 200 nM in ethylene glycol
dimethyl ether and 50 lL of the 200 nM solution was
added to each well. Final cortisone concentration in
the assay was 40 nM. Cells were incubated for 2 h
at 37 ꢁC/5% CO2. At the end of the incubation, ste-
roids in media were extracted with three volumes of
ethyl acetate. The organic phase was transferred to a
fresh tube, dried, resuspended in 5 lL methanol, and
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