Synthesis and activities of oxidative metabolites of the anti-arthritic drug candidate S-2474

Article abstract of DOI:10.1016/S0968-0896(03)00141-X

We have synthesized and characterized some oxidative metabolites of S-2474. In this study, we discovered a novel skeleton, the 2,3-dihydrobenzofuran derivative, which inhibited PGE₂ production at a very low concentration and was effective in th

Full text of DOI:10.1016/S0968-0896(03)00141-X

Bioorganic & Medicinal Chemistry 11 (2003) 2415–2419
Synthesis and Activities of Oxidative Metabolites of the
Anti-arthritic Drug Candidate S-2474
Masanao Inagaki,a,* Hirokuni Jyoyama,a Takashi Ono,a Katsutoshi Yamada,a
Mika Kobayashi,a Takahiko Baba,b Akira Touchi,b Kouji Iwatani,b Tomoyuki Ohkawa,b
Saichi Matsumotoa and Tatsuo Tsuria,*
aDiscovery Research Laboratories, Shionogi & Co., Ltd., Fukushima-ku, Osaka 553-0002, Japan
bDevelopmental Research Laboratories, Shionogi & Co., Ltd., Futaba-cho, Toyonaka, Osaka 561-0825, Japan
Received 9 January 2003; accepted 25 February 2003
Abstract—We have synthesized and characterized some oxidative metabolites of S-2474. In this study, we discovered a novel skel-
eton, the 2,3-dihydrobenzofuran derivative, which inhibited PGE2 production at a very low concentration and was effective in the
anti-carrageenin footpad edema assay.
# 2003 Elsevier Science Ltd. All rights reserved.
Chemistry
Introduction
The tert-butyl-hydroxylated S-2474 (2) was synthesized by
S-2474 [(E)-2-ethyl-5-(3,5-di-tert-butyl-4-hydroxy-ben-
zylidene)-1,2-isothiazolidine 1,1-dioxide, 1], developed
in our laboratories,1 is a cytokine suppressive dual
inhibitor of cyclooxygenase-2 (COX-2) and 5-lipoxy-
genase (5-LO). Drugs are often subjected to metabolic
transformation such as oxidation, reduction or con-
jugate formation. These metabolites may circulate in the
bloodstream and be distributed to the site of pharma-
cological activity. In this work, we studied the metabo-
lism of S-2474 in vitro. HPLC analysis from in vitro
metabolic studies with human and rat liver microsomes,
revealed the presence of two major (M-1 and M-2) and
some minor metabolites. The three portions of S-2474
which may be metabolized by CYPs are shown in Fig-
ure 1 in comparison with findings from metabolic stud-
ies of this class of compounds.2,3 Pathway A is
hydroxylation of the tert-butyl group and further dehy-
dration, giving compounds 2 and 3, respectively. Path-
ways B and C are hydroxylations of a-positions of
nitrogen atom, giving compounds 5 and 6, respectively
(Fig. 2).
a very recently reported method, in which the tert-butyl-
hydroxylated di-tert-butyl-hydroxybenzaldehyde (7) was
used (Scheme 1).4 Compound 3 was easily prepared from 2
by intra-molecular etherealization under the mesylation
condition.2 The de-ethyl S-2474 (5) was prepared by the
improved method described in Scheme 2. This route is
much more effective with respect to E-selectivity and yield
than the previous method.1 The 3-hydroxylated S-2474 (6)
was synthesized in a straightforward manner by the meth-
ods summarized in Scheme 3. A Weinreb amide5 14 was
treated with an a-sulfonyl carbanion to react cleanly and
produce an adduct.6 The adduct was treated with
BrCH2CO2But to give a mono-alkylated derivative as a
single product 15 in 75% yield in two steps. Compound
15 was subjected to NaBH4 reduction and hydro-
genolysis with Pearlman’s catalyst7 to afford compound 16
in 84% yield. Removal of two protecting groups of 16 with
excess iodotrimethylsilane (TMSI) and subsequent treat-
ment of DBU gave an E-benzylidene derivative (17) in
57% yield via a lactone intermediate. Intramolecular
cyclization of 17 was achieved by treatment with ethyl
chloroformate via a mixed-anhydride intermediate to
afford 18 in good yield (90%).8 The 3-hydroxylated S-2474
(6) could be obtained by DIBAL reduction of 18 at ꢀ78ꢁC
in 87% yield. NMRanalysis revealed that the reduction
product existed as an equilibrium mixture between the
ring-opened aldehyde (60) and the ring-closed aminal (6).
*Corresponding authors. Tel.: +81-6-6458-5861; fax: +81-6-6458-
0987; e-mail: masanao.inagaki@shionogi.co.jp (M. Inagaki); tatsuo.
tsuri@shionogi.co.jp (T. Tsuri).
0968-0896/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0968-0896(03)00141-X

2416
M. Inagaki et al. / Bioorg. Med. Chem. 11 (2003) 2415–2419
synthetic, oxidative derivatives of S-2474 were evaluated
for in vitro efficacy according to a previously reported
method.1 The results are summarized in Table 1. Com-
pounds 2 (M-2) and its dehydrating derivative 3 were
revealed to be potent inhibitors of PGE2 production
equal to or slightly higher than the parent compound.
However, these two compounds were not as effective
for LTB4 production as the parent. These synthetic
compounds were revealed to be not effective for LTB4
and/or IL-1 production. The oral anti-inflammatory
activities were further evaluated by carrageenin-
induced foot-pad edema assay. The in vivo results are
summarized in Table 2. Although all the oxidative
derivatives were revealed to be less effective than
S-2474, the 2,3-dihydrofurane derivative 3, which had
lost any antioxidant characteristics, displayed moderate
activity in both in vitro and in vivo assays. This is
noteworthy, because the antioxidant and radical
scavenging property of 2,6-di-tert-butylphenol groups
have been suggested to be relevant to the anti-inflam-
matory efficacy.9 Other groups have reported that
Figure 1.
Results and Discussion
M-1 and M-2 were identified as the de-ethyl S-2474 (5)
and the tert-butyl-hydroxylated S-2474 (2) by HPLC
analysis, respectively. However, compounds 3 and 6
were not identical to any minor metabolites of S-2474
by HPLC comparison. Structure elucidation of the
unknown minor metabolites is now in progress. These
Figure 2.
Scheme 1. Reagents and conditions: (a) dihydropyran, PPTS, CH2Cl2, rt (97%); (b) LDA, THF ꢀ78 ꢁC; (c) MsCl, Et3N, AcOEt, 0 ꢁC; (d) p-TsOH,
MeOH, rt (86% for three steps); (e) MsCl, Et3N, CH2Cl2, 0 ꢁC (94%).

M. Inagaki et al. / Bioorg. Med. Chem. 11 (2003) 2415–2419
2417
Scheme 2. Reagents and conditions: (a) LHMDS, THF, ꢀ78 ꢁC; (b) MsCl, Et3N, AcOEt, 0 ꢁC (70% for two steps); (c) TFA, anisole, CH2Cl2, rt
(95%). BH, benzhydryl.
Scheme 3. Reagents and conditions: (a) CH3SO2N(BH)Et, LHMDS, THF, ꢀ50 ꢁC; (b) BrCH2CO2But, K2CO3, DMF, rt (75% for two steps);
(c) NaBH4, CH2Cl2-MeOH, rt; (d) Pd(OH)2/C, THF-MeOH, H2, rt (84% for two steps); (e) TMSI, CHCl3, 0 ꢁC; (f) DBU, benzene; rt (57% for two
steps); (g) ClCO2Et, Et3N, CH2Cl2, 0 ꢁC (90%); (h) DIBALH, CH2Cl2, ꢀ78 ꢁC (87%). BH, benzhydryl.
Table 1. In vitro inhibitory effects on production of PGE2, LTB4,
and IL-1 by oxidative derivatives of S-2474
Table 2. In vivo anti-inflammatory effects of oxidative derivatives of
S-2474
Compd
Inhibition of
PGE2 production
IC50, mMa
Inhibition of LTB4 Inhibition of IL-1
production
Compd
Anti-edema (carrageenin)
% inhib. at 30 mg/kga
ED30 (mg/kg)b
production
IC50, mMc
IC50, mMb
1
2
3
5
6
37.8**
60.3**
50.1**
17.2
3.5
6.6
N.D.c
1
2
3
5
6
0.0095
0.005
0.002
0.03
2.5
44
10
15
>100
>100
2.7
33
>100
69
28.6**
>1.0
aPercent inhibition of carrageenin-induced footpad edema at 30 mg/kg
po.
aConcentration (mM) required for 50% inhibition of PGE2 formation
in rat synovial cells.
bThe dose (mg/kg) required for 30% inhibition of carrageenin-induced
edema.
bConcentration (mM) required for 50% inhibition of LTB4 formation
in rat peritoneal cells.
cNot determined.
cConcentration (mM) required for 50% inhibition of IL-1 formation in
human THP-1 cells.
compounds with this functionality discovered from
metabolic studies of the di-tert-butylphenol class com-
pound tebufelone are dual inhibitors of COX and
5-LO.10
and IL-1. However, we discovered that a novel, non-
antioxidant skeleton, the 2,3-dihydrobenzofuran deri-
vative 3, was a potent inhibitor of PGE2 production and
effective in the anti-inflammation animal model.
This study has clarified the primary major metabolic
pathways of S-2474: metabolic oxidation via pathways A
and B in Figure 1. The presence of the metabolites should
not modify the antiinflammatory effect of S-2474 because
they do not have potent effects on the production of LTB4
Experimental
1
Melting points are uncorrected. H NMRspectra were
determined at 200 or 300 MHz and 13C NMRspectra

2418
M. Inagaki et al. / Bioorg. Med. Chem. 11 (2003) 2415–2419
were determined at 75.5MHz with tetramethylsilane as an
internal standard. Unless otherwise stated, all reactions
were carried out under a nitrogen atmosphere with guar-
anteed grade solvents that had been dried over type 4A or
3A molecular sieves. Drying of organic extracts over
anhydrous sodium sulfate is simply indicated by the word
‘dried’. Column chromatography using silica gel (230–400
mesh) is referred to as ‘chromatography on silica gel’.
1434, 1377, 1314, 1242, 1215, 1157 cmꢀ1. Anal. calcd for
C31H37NO3S: C, 73.92; H, 7.40; N, 2.78; S, 6.37. Found:
C, 73.68; H, 7.23; N, 2.83; S, 6.26.
(E)-5-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-1,2-iso-
thiazolidine 1,1-dioxide (5).1 A mixture of 13 (10.88 g,
21.6 mmol), TFA (12.6 mL, 164 mmol), anisole (11 mL,
101 mmol), and CH2Cl2 (20 mL) was stirred at 23 ꢁC for
1 h. The solid NaHCO3 (13.7 g) was carefully added and
then cold water and toluene (100 mL) were added. A
precipitate was collected and washed with water and
toluene to give the title compound (6.94 g, 95%) as a
colorless solid.
(E)-5-(7-tert-Butyl-3,3-dimethyl-2,3-dihydrobenzofuran-
5-ylmethylene)-2-ethyl-1,2-isothiazolidine 1,1-dioxide (3)
Methansulfonyl chloride (0.39 mL, 4.98 mmol) was
added to a stirred solution of 24 (1.58 g, 4.15 mmol),
triethylamine (1.45 mL, 12.5 mmol), and CH2Cl2
(10 mL) at 0 ꢁC and stirred for 0.5 h. To the reaction
mixture were added dil. HCl and AcOEt and the
organic layer was separated and washed with H2O and
brine, dried and evaporated. The residue was subjected
to chromatography on silica gel (n-hexane/AcOEt
70:30) to give the title compound as a colorless solid
(1.41 g, 94%). Mp 107–109 ꢁC. 1H NMR(CDCl 3): d
1.29 (t, J=7.2 Hz, 3H), 1.33 (s, 6H), 1.35 (s, 9H), 3.06–
3.33 (m, 6H), 4.28 (s, 2H), 7.01 (d, J=1.6 Hz, 1H), 7.15
(d, J=1.6 Hz, 1H), 7.25 (t, J=2.4 Hz, 1H). 13C NMR
(CDCl3): d 12.89, 23.87, 27.49, 29.10, 34.15, 39.21,
41.23, 43.77, 84.24, 121.34, 126.08, 127.11, 131.01,
131.11, 133.39, 137.82, 158.44. IR(KBr): 3436, 2963,
2871, 1642, 1602, 1453, 1288, 1151 cmꢀ1. Anal. calcd for
C20H29NO3S: C, 66.08; H, 8.04; N, 3.85; S, 8.82. Found:
C, 65.89; H, 8.01; N, 3.84; S, 8.79.
3-(Benzhydryl-ethyl-sulfamoyl)-4-(3,5-di-tert-butyl-4-
methoxymethoxyphenyl)-4-oxo-butyric acid tert-butyl es-
ter (15). To a stirred solution of N-benzhydryl-N-ethyl-
methansulfonamide (16.82 g, 58mmol) and THF
(200mL) was added LHMDS solution (1 M in THF,
64mL, 64mmol) at ꢀ50ꢁC and the resulting mixture was
stirred for 0.5 h at ꢀ50ꢁC. A solution of Weinreb amide
14 (17.7 g, 52.2 mmol) in THF (100mL) was slowly added
to the above reaction mixture at ꢀ50ꢁC. The mixture was
allowed to warm to 23ꢁC and poured into satd NH4Cl
solution. A product was extracted with AcOEt, and the
organic layer was washed successively with satd NaHCO3
and brine. After drying and removal of solvents, a residual
oil was obtained. The residue was treated with tert-butyl
bromoacetate (9.25 mL, 57.3 mmol), K2CO3 (9.89 g,
71.6mmol) in DMF at 23 ꢁC for 18 h. To the reaction
mixture were added H2O and AcOEt. The organic layer
was separated and washed with H2O and brine, dried
and evaporated to give a yellow crystalline residue,
which was washed well with n-hexane to give the title
compound (26.75 g, 75%). Mp 104–105 ꢁC. 1H NMR
(CDCl3): d 0.77 (t, J=7.7 Hz, 3H), 1.21 (s, 9H), 1.44 (s,
18H), 2.83 (dd, J=3.2, 16.8 Hz, 1H), 3.29–3.51 (m, 3H),
3.65 (s, 3H), 4.90 (s, 2H), 5.28 (dd, J=3.2, 10.4Hz, 1H),
6.39 (s, 1H), 7.31–7.34 (m, 10H), 7.96 (s, 2H). IR(CHCl 3):
3435, 1735, 1677, 1340, 1164, 1147cmꢀ1. Anal. calcd for
C39H53NO7S: C, 68.90; H, 7.86; N, 2.06; S, 4.72. Found:
C, 68.80; H, 7.93; N, 2.16; S, 4.55.
2-Benzhydryl-1,2-isothiazolidine 1,1-dioxide (12).
A
solution of 3-chloropropanesulfonyl chloride (20 g,
113 mmol) in AcOEt (50 mL) was added to a stirred
mixture of diphenylmethylamine (22.78 g, 124 mmol),
triethylamine (18.9 mL, 136 mmol) in AcOEt (100 mL)
at 5 ꢁC. The resulting mixture was stirred for 0.5 h at
23 ꢁC. The reaction mixture was washed successively
with diluted HCl, H2O and brine. The organic layer was
dried and evaporated to give a crystalline residue. The
residue was treated with K2CO3 (31.2 g, 226 mmol) and
methyl ethyl ketone at refluxing temperature for 18 h.
After being cooled to rt, the mixture was passed
through a pad of silica gel and the filtrate was con-
centrated to give a crystalline residue that was recrys-
tallized from AcOEt to give the title compound (24.8 g,
4-(3,5-Di-tert-butyl-4-methoxymethoxyphenyl)-3-ethyl-
sulfamoyl-4-hydroxy-butyric acid tert-butyl ester (16).
NaBH4 (1.89 g, 49.9 mmol) was slowly added to a solu-
tion of 15 (22.6 g, 33.2 mmol) in MeOH (150 mL) and
CH2Cl2 (180 mL) at 0 ꢁC. The reaction was allowed to
warm to 23 ꢁC and stirred for an additional 0.5 h. Ace-
tone (5 mL) and then satd NH4Cl solution and CH2Cl2
were added to the reaction mixture. The organic layer
was separated and washed with H2O and brine, dried
and evaporated to give an almost colorless solid. The
residue was dissolved with THF (100 mL) and MeOH
(200 mL) and treated with Perlman’s catalyst (3.05 g)
under H2 atmosphere for 5 h at 23 ꢁC. The catalyst was
removed by filtration and the filtrate was concentrated
to afford a crystalline residue, which was recrystallized
from ether and n-hexane to give the pure title com-
76%) as a colorless crystal. Mp 148–151 ꢁC. H NMR
1
(DMSO-d6): d 2.22 (quintet, J=6.9 Hz, 2H), 3.00 (t,
J=6.9 Hz, 2H), 3.26 (t, J=7.2 Hz, 2H), 5.77 (s, 1H),
7.26–7.39 (m, 10H). IR(Nujol): 2925, 1455, 1445, 1377,
1287, 1201, 1166, 1138 cmꢀ1
.
Anal. calcd for
C16H17NO2S: C, 66.87; H, 5.96; N, 4.87; S, 11.16.
Found: C, 66.71; H, 5.83; N, 4.85; S, 11.05
(E)-2-Benzhydryl-5-(3,5-di-tert-butyl-4-hydroxybenzyli-
dene)-1,2-isothiazolidine 1,1-dioxide (13). The title com-
pound was prepared in 70% yield from 11 and 12 by the
previously reported method with LHMDS as a base
instead of LDA.4 Mp 192–193 ꢁC. H NMR(CDCl ): d
pound (13.7 g, 84%). Mp 96–97 ꢁC. H NMR(CDCl ):
1
1
3
3
1.43 (s, 18H), 3.04 (dt, J=2.1, 6.0 Hz, 2H), 3.17 (t,
J=6.0 Hz, 2H), 5.49 (s, 1H), 5.99 (s, 1H), 7.21 (s, 2H),
7.24–7.38 (m, 11H). IR(Nujol): 3599, 2925, 1597, 1455,
d 1.15 (t, J=7.4 Hz, 3H), 1.36 (9H, s), 1.44 (s, 18H), 2.31
(dd, J=5.6, 17.6 Hz, 1H), 2.80 (dd, J=6.6, 17.6 Hz, 1H),
3.00–3.27 (m, 2H), 3.40 (d, J=4.8 Hz, 1H), 3.64 (s, 3H),

M. Inagaki et al. / Bioorg. Med. Chem. 11 (2003) 2415–2419
2419
3.97 (ddd, J=5.6, 6.6, 8.2 Hz, 1H), 4.19–4.25 (m, 1H), 4.89
(s, 2H), 4.95 (dd, J=4.8, 8.2Hz, 1H), 7.27 (s, 2H). IR
of 6; d 1.27 (t, J=7.0 Hz, 3H), 1.48 (s, 18H), 3.07 (dt,
J=2.4, 16.4 Hz, 1H), 3.27 (q, J=7.0 Hz, 2H), 3.57 (ddd,
J=2.4, 6.2, 16.4 Hz, 1H), 5.23 (m, 1H), 5.35 (br s, 1H),
7.18 (t, J=2.4 Hz, 1H), 7.37 (s, 2H); peaks of 60; d 1.12–
1.21 (m, 3H), 1.44 (s, 18H), 2.95–3.05 (m, 2H), 3.78 (d,
J=1.6 Hz, 2H), 7.30 (s, 2H), 7.68 (br s, 1H), 9.78 (t,
J=1.6 Hz, 1H). IR(KBr): 3610, 3427, 2968, 1653, 1595,
(KBr): 3441, 3298, 2966, 1736, 1635, 1367, 1152 cmꢀ1
.
Anal. calcd for C26H45NO7S: C, 60.56; H, 8.80; N, 2.72; S,
6.22. Found: C, 60.37; H, 8.72; N, 2.69; S, 6.17.
(E)-4-(3,5-Di-tert-butyl-4-hydroxyphenyl)-3-ethylsulfa-
moyl-3-butenoic acid (17). To a stirred solution of 16
(1.10 g, 2.13 mmol) in CHCl3 (30 mL) was added TMSI
(0.91 mL, 6.39 mmol) in one portion with ice-cooling
and stirred for 0.5 h. To the reaction were added 5%
aqueous sodium thiosulfate and CH2Cl2, and an organic
layer was separated and washed with brine, dried and
evaporated. The obtained residue was purified by col-
umn chromatography on silica gel to give an inter-
mediate lactone (481 mg, 58%) as a colorless solid. Mp
129–131 ꢁC. The lactone (1.52 g, 3.81 mmol) was treated
with DBU (1.14 mL, 7.62 mmol) in benzene (50 mL) at
0 ꢁC for 0.5 h. To the reaction were added 1 N HCl and
AcOEt, and an organic layer was separated and washed
with water and brine, dried and evaporated to afford the
title compound (1.52 g, quant) as a colorless solid. Mp
1432, 1261, 1214, 1147 cmꢀ1
.
Anal. calcd for
C20H31NO4S: C, 62.96; H, 8.19; N, 3.67; S, 8.40. Found:
C, 63.075; H, 8.26; N, 3.67; S, 8.33.
Acknowledgements
The authors thank Drs. Mitsuaki Ohtani, Kenji
Kawada, and Norihiko Tanimoto for their encourage-
ment and helpful discussions throughout this study.
References and Notes
1. Inagaki, M.; Tsuri, T.; Jyoyama, H.; Ono, T.; Yamada, K.;
Kobayashi, M.; Hori, Y.; Arimura, A.; Yasui, K.; Ohno, K.;
Kakudo, S.; Koizumi, K.; Suzuki, R.; Kato, M.; Kawai, S.;
Matsumoto, S. J. Med. Chem. 2000, 43, 2040.
2. Miller, J. A.; Matthews, R. S. J. Org. Chem. 1992, 57, 2514.
and references cited therein.
3. Ikuta, H.; Yamagishi, Y.; Akasaka, M.; Yamatsu, I.;
Kobayashi, S.; Yoda, H.: Katayama, K. JP Patent 115,860,
1988.
ꢁ
1
169–172 C. H NMR(CD OD): d 1.15 (t, J=7.4 Hz,
3
3H), 1.43 (s, 18H), 2.99 (q, J=7.4 Hz, 2H), 3.63 (s, 2H),
7.29 (s, 2H), 7.58 (s, 1H). IR(KBr): 3604, 3267, 2958,
1719, 1631, 1596, 1430, 1326, 1158 cmꢀ1. Anal. calcd for
C20H31NO5S: C, 60.43; H, 7.86; N, 3.52; S, 8.07. Found:
C, 60.36; H, 7.95; N, 3.54; S, 7.87.
(E)-5-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-
1,2-isothiazolidine-3-one 1,1-dioxide (18). To a stirred
solution of 17 (1.52 g, 3.81 mmol), triethylamine
(0.74 mL, 5.72 mmol) and CH2Cl2 (60 mL) was added
ethyl chloroformate (0.44 mL, 4.57 mmol) at 0 ꢁC, and
stirring was continued for 50 min. To the reaction mix-
ture were added water and CH2Cl2. An organic layer
was separated and washed with brine, dried and evapo-
rated to give a crystalline residue, which was washed
with ether to afford the title compound (1.30 g, 90%) as
4. Inagaki, M.; Matsumoto, S.; Tsuri, T. J. Org. Chem. 2003,
68, 1128.
5. Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1982, 22, 3815.
6. LHMDS is a good base in this reaction. When LDA was
used as a base, according to our previous report,1 a methine
proton of the benzhydryl protecting group was deprotonated
at ꢀ78 ꢁC and the reaction did not proceed cleanly.
7. Poss, M. A.; Reid, J. A. Tetrahedron Lett. 1992, 33, 7291.
8. (a) Gut, V.; Rudinger, J.; Walter, R.; Herling, P. A.;
Schwartz, I. L. Tetrahedron 1968, 24, 6351. (b) Brkic, Z.;
Herak, J. J.; Mandic, Z.; Lukic, I.; Tomic, M.; Kovacevic, M.
Tetrahedron 1993, 49, 9801.
a colorless crystal. Mp 188–190 ꢁC. H NMR(CDCl ):
1
3
9. Swingle, K. F.; Bell, R. L.; Moore, G. G. Antiinflammatory
Activity of Antioxidants. Antiinflammatory and Anti-Rheu-
matic Drugs; Rainsford, K. D. Ed.; CRC: Boca Raton, FL,
1985; Vol. III, p. 105.
d 1.38 (t, J=7.2 Hz, 3H), 1.46 (s, 18H), 3.74 (q,
J=7.4 Hz, 2H), 3.80 (d, J=2.4 Hz, 2H), 5.64 (s, 1H),
7.23 (s, 2H), 7.45 (t, J=2.4 Hz, 1H). IR(KBr): 3559,
2960, 1715, 1641, 1598, 1434, 1317, 1159 cmꢀ1. Anal.
calcd for C20H29NO4S: C, 63.30; H, 7.70; N, 3.69; S,
8.45. Found: C, 63.07; H, 7.71; N, 3.72; S, 8.30.
10. (a) Janusz, J. M.; Young, P. A.; Ridgeway, J. M.; Scherz,
M. W.; Enzweiler, K.; Wu, L. I.; Gan, L.; Darolia, R.; Mat-
thews, R. S.; Hennes, D.; Kellstein, D. E.; Green, S. A.;
Tulich, J. L.; Rosario-Jansen, T.; Magrisso, I. J.; Wehmeyer,
K. R.; Kuhlenbeck, D. L.; Eichhold, T. H.; Dobson, R. L. M.;
Sirko, S. P.; Farmer, R. W. J. Med. Chem. 1998, 41, 1112.
(b) Janusz, J. M.; Young, P. A.; Ridgeway, J. M.; Scherz,
M. W.; Enzweiler, K.; Wu, L. I.; Gan, L.; Pikul, S.; McDow-
Dunham, K. L.; Johnson, C. R.; Senanayake, C. B.; Kell-
stein, D. E.; Green, S. A.; Tulich, J. L.; Rosario-Jansen, T.;
Magrisso, I. J.; Wehmeyer, K. R.; Kuhlenbeck, D. L.;
Eichhold, T. H.; Dobson, R. L. M. J. Med. Chem. 1998,
41, 1124. (c) Janusz, J. M.; Young, P. A.; Ridgeway, J. M.;
Scherz, M. W.; Enzweiler, K.; Wu, L. I.; Gan, L.; Chen, J.;
Kellstein, D. E.; Green, S. A.; Tulich, J. L.; Rosario-Jansen,
T.; Magrisso, I. J.; Wehmeyer, K. R.; Kuhlenbeck, D. L.;
Eichhold, T. H.; Dobson, R. L. M. J. Med. Chem. 1998, 41,
3515.
(E)-5-(3,5-Di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-3-
hydroxy-1,2-isothiazolidine 1,1-dioxide (6) and (E)-4-(3,
5-Di-tert-butyl-4-hydroxyphenyl)-3-ethylsulfamoyl-3-bu-
tenal (60). To a stirred solution of 18 (870 mg, 2.29 mol)
in CH2Cl2 (30 mL) was added DIBALH solution (1 M
in n-hexane, 4.22 mL, 4.22 mmol) at ꢀ40 ꢁC and stirred
for 5 min. To the reaction mixture was added satd
NH4Cl, and the mixture was allowed to warm to 23 ꢁC
slowly. A slurry was removed by filtration and the fil-
trate was concentrated to give a crystalline residue,
which was recrystallized from ether and n-hexane to
give the title compound (762 mg, 87%) as a colorless
crystal. Mp 138–141 ꢁC. 6 : 60=5:1 in acetone-d6; peaks