Novel lβ-methylcarbapenems having cyclic sulfonamide moieties: Synthesis and evaluation of in vitro antibacterial activity

Article abstract of DOI:10.1016/j.ejmech.2007.02.001

The synthesis of a new series of 1β-methylcarbapenems having cyclic sulfonamide moieties is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituent on the pyrrolidi

Full text of DOI:10.1016/j.ejmech.2007.02.001

European Journal of Medicinal Chemistry 42 (2007) 1176e1183
http://www.elsevier.com/locate/ejmech
Original article
Novel lb-methylcarbapenems having cyclic sulfonamide moieties:
Synthesis and evaluation of in vitro antibacterial activity
Seong Jong Kim a, Hyeong Beom Park b, Jae Seoung Lee a, Nam Hyun Jo a, Kyung Ho Yoo a,
Daejin Baek c, Byoung-won Kang d, Jung-Hyuck Cho a, Chang-Hyun Oh a,
*
a Medicinal Chemistry Research Center, Korea Institute of Science and Technology, Seoul 130-650, South Korea
b Department of Chemistry, Hanyang University, Seoul, South Korea
c Department of Chemistry, Hanseo University, Seosan, South Korea
d Department of Chemistry, Dong-eui University, Busan, South Korea
Received 26 October 2006; received in revised form 31 January 2007; accepted 1 February 2007
Available online 2 March 2007
Abstract
The synthesis of a new series of 1b-methylcarbapenems having cyclic sulfonamide moieties is described. Their in vitro antibacterial activities
against both Gram-positive and Gram-negative bacteria were tested and the effect of substituent on the pyrrolidine ring was investigated. A par-
ticular compound (IIIi) having 2-methyl-[1,2,6]thiadiazinan-1,1-dioxide moiety showed the most potent antibacterial activity.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: 1b-Methylcarbapenems; Antibacterial activity; Substituent effects
OH
O
OH
O
CH3
CH3
O
O
1. Introduction
S
S
N
N
H
COONa
N
N
NH
NH
Carbapenems are one of the most potent types of antibacte-
rial agents and are among those used as a last resort against
infections in the clinical field. Three carbapenems, imipenem
[1,2], meropenem (1) [3], and ertapenem (2) [4] have been
marketed so far. At present, several carbapenem derivatives
such as S-4661 (3) [5], BO-2727 [6] and E-1010 [7] are under
clinical or preclinical studies since the launch of meropenem.
We were also reported [8e12] that the carbapenem com-
pounds having a pyrrolidin-3-ylthio group at the C-2 position
in the carbapenem skeleton are noted for their broad and po-
tent antibacterial activity.
COOH
COOH
1, Meropenem
2, Ertapenem
OH
CH3
S
NHSO2NH2
N
NH
O
COOH
3, S-4661
2. Chemistry
In this paper, we describe the synthesis and structureeactiv-
ity relationships of lb-methylcarbapenems having a 50-cyclic
sulfonamide moieties as a C-2 side chain and our approach for
improvement of antibacterial activity of the carbapenems is
discussed.
Our general synthetic route leading to new carbapenems in-
volved the preparation of appropriately protected thiols contain-
ing pyrrolidine ring as a side chain and coupling reaction with
the carbapenem diphenylphosphate, followed by deprotection
of the resulting protected carbapenems in a usual manner.
The substituted sulfamides 3aed, 3f and 3i were easily ac-
cessible by the condensation of the corresponding diamines
* Corresponding author. Tel.: þ82 2 958 5160.
E-mail address: choh@kist.re.kr (C.-H. Oh).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.02.001

S.J. Kim et al. / European Journal of Medicinal Chemistry 42 (2007) 1176e1183
1177
Cl
1aed, 1f and 1i with sulfamide itself in refluxing pyridine
(Scheme 1).
iii
H
N
O
HN
HN
N
O
i
The other cyclic sulfamides 3e and 3h were also synthe-
sized by the improved procedure as shown in Scheme 2. The
intermediates 5e and 5h were directly synthesized by reaction
of the corresponding mustards with BOCesulfamoyl chloride.
The N-BOC cyclic sulfamides 3e and 3h were obtained in high
yield by treatment of 5e and 5h with K2CO3 in DMSO.
The cyclic sulfamidate 3g ([1,2,3]oxathiadiazolidin-2,2-
dioxide) is typically prepared as shown in Scheme 3. The sul-
famidite 7 was obtained by reaction of N-protected amino
ethanol and SOCl2 in CH3CN at low temperature. The oxida-
tion of the sulfamidite 7 with RuO4 in CH3CN gave sulfami-
date 8, which was successfully converted into the deprotected
cyclosulfamidate 3g using trifluoroacetic acid.
BOC
BOC
S
O
S
C O
O
Cl S N
O
O
5e
3e
4
ii
Cl
iii
H
N
HN
HN
N
O
S
BOC
BOC
S
O
O
O
5h
3h
i) BuOH, 2 -chloroethylamine, CH2Cl2 ii) BuOH, 2-chloropropylamine, CH2Cl2 iii) K2CO3, DMSO
Scheme 2.
Ester compound 9 was reduced with lithium borohydride
in THF/EtOH and subsequently mesylated to give 11. The
O-mesylated compound 11 was treated with cyclosulfamides
and sodium hydride in DMF to provide 12aei. Deprotection
of the trityl group to mercaptans (Iaei) was achieved by treat-
ment of 12aei with trifluoroacetic acid in the presence of trie-
thylsilane (Scheme 4).
Finally, the reaction of 13 [13] with thiols Iaei in the pres-
ence of diisopropylethylamine provided the 2-substituted
carbapenems IIaei. Deprotection of these compounds by tetra-
kis(triphenylphosphine)palladium(0) and tributyltin hydride
gave the crude products, which were purified by HP-20 column
to give the pure carbapenems IIIaei (Scheme 5).
activities against Gram-positive to meropenem, and against
Gram-negative bacteria except Pseudomonas aeruginosa to
imipenem.
As to the substituent on the pyrrolidine chain, compounds
IIIhei having thiadiazinane moieties were generally more po-
tent than the thiadiazolidine compounds IIIaeb and IIIe. The
introduction of alkyl group at N-position of thiadiazolidine
(IIIa and IIIb) led to significantly enhanced antibacterial ac-
tivity compared to compounds (IIIced) with alkyl substitute
at C-3 position. As expected, the existence of N-benzyl group
(IIIf) significantly lowered the antibacterial activity compared
to compounds (IIIaeb) with methyl and ethyl groups.
Comparative in vitro activities of IIIi, meropenem, and imi-
penem against 40 bacterial strains are summarized in Table 2.
The selected carbapenem IIIi possessed excellent in vitro ac-
tivity against 40 target pathogens except P. aeruginosa, and su-
perior or similar antibacterial activities against Gram-positive
bacteria to meropenem, and against Gram-negative bacteria
to imipenem. Against Escherichia coli and Corynebacterium
diphtheriae, IIIi was 2e3 times more active than the compared
meropenem and imipenem.
2.1. Biological activity
The MICs were determined by the agar dilution method us-
ing test agar. An overnight culture of bacteria in tryptosoy
broth was diluted to about 106 cells/mL with the same broth
and inoculated with an inoculating device onto agar containing
serial twofold dilutions of the test compounds. Organisms
were incubated at 37 ꢀC for 18e20 h. The MICs of a com-
pound were defined as the lowest concentration that visibly in-
hibited growth.
3. Experimental
The in vitro antibacterial activities of the new carbapenems
(IIIaei) prepared above against both Gram-positive and
Gram-negative bacteria are listed in Table 1. For comparison,
the MIC values of imipenem and meropenem are also listed.
All the compounds displayed superior or similar antibacterial
Melting point (mp) was measured by Thomas Hoover appa-
ratus and was uncorrected. UV spectra were recorded on Hew-
lett Packard 8451A UVeVIS spectrophotometer. IR spectra
were recorded on Perkin Elmer 16F-PC FT-IR. NMR spectra
were recorded on Varian Gemini 300 spectrometer with tetra-
methylsilane (TMS) as an internal standard. The mass spec-
trometry system was based on an HP5989A MS Engine (Palo
Alto, CA, USA) mass spectrometer with an HP Model 59987A.
O
N
O
S
R
RHN
NH2
( )
O
O
pyridine
reflux
NH
S
+
n
( )
H2N
NH2
n
R1 R2
R1 R2
3.1. 2-Methyl-[1,2,5]thiadiazolidin-1,1-dioxide (3a)
1a-d, 1f and 1i
2
3a-d, 3f and 3i
a: n=1, R=Me, R1=R2=H
b: n=1, R=Et, R1=R2=H
c: n=1, R=H, R1=Me, R2=H
d: n=1, R=H, R1=R2=Me
f: n=1, R=Bn, R1=R2=H
i: n=2, R=Me, R1=R2=H
To a refluxing solution of sulfamide (1.09 g, 11.3 mmol) in
anhydrous pyridine (30 mL) was added dropwise anhydrous N-
methylenediamine (1a, 0.84 g, 11.3 mmol) for over 2 h. The
resulting mixture was refluxed for further 16 h under nitrogen
before the solvent was removed under vacuum. The residue
was triturated with hexane and the solids were collected by
Scheme 1.

1178
S.J. Kim et al. / European Journal of Medicinal Chemistry 42 (2007) 1176e1183
O
O
O
O
O
O
O
S
S
S
BOC
BOC
i
ii
iii
BOC NH
OH
HN
N
N
O
6
7
8
3g
i) SOCl2, CH3CN ii) NaIO4, RuCl3, CH3CN iii) TFA
Scheme 3.
filtration and purified by flash chromatography (CH2Cl2/
MeOH ¼ 20:1) to give 76% yield of 3a as a white solid: mp
3.2. 1-tert-Butoxycarbonyl-[1,2,5]thiadiazolidin-
1,1-dioxide (3e)
1
80e83 ꢀC. H NMR (CDCl3): d 2.74 (s, 3H), 3.37e3.39 (dd,
2H, J ¼ 1.2 and 2.1 Hz), 3.52 (q, 2H), 4.79 (bs, 1H). 13C
To a stirred solution of chlorosulfonyl isocyanate (CSI) (4,
4.00 g, 2.8 mmol) in 80 mL of anhydrous dichloromethane at
0 ꢀC was added 3.3 mmol of absolute tert-butyl alcohol in the
same solvent. After being stirred for 30 min, the resulting so-
lution of BOCesulfamoyl chloride and 19.7 mL of triethyl-
amine in 10 mL of dichloromethane were added dropwise to
3.3 mmol of a suspended amino acid ester (2-chloroethyl-
amine or 3-chloropropylamine) hydrochloride in 30 mL of
dichloromethane. The reaction temperature did not rise above
5 ꢀC. The resulting reaction solution was allowed to warm up
to room temperature for over 2 h. The reaction mixture was
diluted with 100 mL of dichloromethane, washed with 0.1 N
HCl solution and brine. The organic layer was dried
(MgSO4) and concentrated in vacuo to give the crude product.
Recrystallization from CH2Cl2 at low temperature afforded the
expected compound 3e (3.1 g, 71%) as a pale yellow solid.
NMR (CDCl3): d 32.67, 39.64, 46.94.
The syntheses of compounds 3bed, 3f and 3i were carried
out by the same procedure as described for the preparation of 3a.
1
3b: Yield 57%. H NMR (CDCl3): d 1.24e1.29 (t, 3H,
J ¼ 14.5 Hz), 3.05e3.12 (q, 2H), 3.34e3.42 (m, 2H), 3.47e
3.54 (m, 2H), 5.31 (bs, 1H). 13C NMR (CDCl3): d 13.18,
39.90, 41.53, 48.41.
1
3c: Yield 46%. H NMR (CDCl3): d 1.34e1.36 (d, 3H,
J ¼ 6.4 Hz), 3.10e3.13 (m, 1H), 3.60 (m, 1H), 3.89e3.93
(m, 1H), 4.70 (bs, 1H), 4.82 (bs, 1H). 13C NMR (CDCl3):
d 18.14, 54.64, 57.94.
1
3d: Yield 76%. H NMR (CDCl3): d 1.43 (s, 6H), 3.32e
3.30 (d, 2H, J ¼ 7.3 Hz), 4.18 (bs, 1H), 4.72 (bs, 1H). 13C
NMR (CDCl3): d 21.40, 51.91, 56.36.
3f: Yield 79%. 1H NMR (CDCl3): d 3.25e3.29 (t, 2H,
J ¼ 13.2 Hz), 3.43e3.50 (m, 2H), 4.17 (s, 2H), 4.58 (bs,
1H), 7.26e7.37 (m, 5H). 13C NMR (CDCl3): d 42.37, 49.65,
50.34, 126.98, 128.32, 130.02, 146.17.
1
mp 143e144 ꢀC. H NMR (CDCl3): d 1.53 (s, 9H), 3.40e
3.44 (t, 2H, J ¼ 12.8 Hz), 3.79e3.84 (t, 2H, J ¼ 12.7 Hz),
4.91 (s, 1H). 13C NMR (CDCl3): d 29.06, 43.89, 46.32,
83.78, 163.28.
1
3i: Yield 71%. H NMR (CDCl3): d 1.74e1.81 (m, 2H),
2.75 (s, 3H), 3.28e3.32 (t, 2H, J ¼ 5.8 Hz), 3.48e3.54 (m,
2H), 4.14 (bs, 1H). 13C NMR (CDCl3): d 28.23, 40.60,
42.11, 44.96.
The synthesis of compound 3h was carried out by the same
procedure as described for the preparation of 3e using the 3-
chloropropylamine.
O
Tr.S
Tr.S
ii
Tr.S
i
OCH3
OMs
OH
N
N
N
AOC
AOC
AOC
9
10
O
O
O
O
iii
iv
S
S
HS
R
TrS
R
N
Z
N
Z
N
R1
( )n
N
R1
( )n
AOC
AOC
R1
R1
12a-i
Ia-i
a: Z=N, n=1, R=Me, R1=R2=H
b: Z=N, n=1, R=Et, R1=R2=H
c: Z=N, n=1, R=H, R1=Me, R2=H
d: Z=N, n=1, R=H, R1=R2=Me
e: Z=N, n=1, R= R1=R2=H
f: Z=N, n=1, R=Bn, R1=R2=H
g: Z=O, n=1, R1=R2=H
h: Z=N, n=2, R=R1=R2=H
i: Z=N, n=2, R=Me, R1=R2=H
i) LiBH4, THF/EyOH ii) MsCl, TEA, CH2Cl2 iii) 3a-i, NaH, DMF iv) Trifluroacetic acid, triethyl silane
Scheme 4.

S.J. Kim et al. / European Journal of Medicinal Chemistry 42 (2007) 1176e1183
1179
OH
O
CH3
OH
O
CH3
OH
O
CH3
O
O
O
O
O
S
S
i
R
ii
S
R
S
O
P(OPh)2
N
( )n
Z
X
N
N
N
N
NH
( )n
N
R1
COOH
R1
COOAllyl
COOAllyl
AOC
R2
R2
13
IIa-i
IIIa-i
a: Z=N, n=1, R=Me, R1=R2=H
b: Z=N, n=1, R=Et, R1=R2=H
c: Z=N, n=1, R=H, R1=Me, R2=H
d: Z=N, n=1, R=H, R1=R2=Me
e: Z=N, n=1, R= R1=R2=H
f: Z=N, n=1, R=Bn, R1=R2=H
g: Z=O, n=1, R1=R2=H
i) N,N'-Diisopropylethyl amine, Ia-i, CH3CN (ii) Tetrakis (triphenylphosphine)palladium, tributyltin hydride, CH2Cl2.
h: Z=N, n=2, R=R1=R2=H
i: Z=N, n=2, R=Me, R1=R2=H
Scheme 5.
1
3h: Yield 57%. H NMR (CDCl3): d 1.52 (s, 9H), 1.82e
1.89 (m, 2H), 3.51e3.53 (t, 2H, J ¼ 5.6 Hz), 3.91e3.95 (m,
2H), 4.49 (bs, 1H). 13C NMR (CDCl3): d 25.53, 29.06,
41.23, 42.01, 81.92, 161.91.
(100 mL), and the two phases were separated. The organic
layer was washed with water (20 mL), saturated aqueous
NaHCO3 and brine. After drying over MgSO4, the filtrate
was then concentrated to afford 8 as an analytically pure color-
less liquid.
1
7: H NMR (CDCl3): d 1.53 (s, 9H), 3.53e3.60 (m, 1H),
3.3. 1-tert-Butoxycarbonyl-[1,2,3]oxathiadiazolidin-
2,2-dioxide (8)
3.84e3.88 (m, 1H), 4.68e4.74 (m, 1H), 4.96e4.98 (m, 1H).
13C NMR (CDCl3): d 27.03, 47.98, 67.68, 82.12, 162.81.
8: Yield 86%. 1H NMR (CDCl3): d 1.45 (s, 9H), 3.26e3.32
(m, 2H), 3.68e3.71 (m, 2H). 13C NMR (CDCl3): d 28.76,
42.49, 61.31, 81.94, 162.84.
A solution of SOCl2 (2.59 mL, 3.5 mmol) in dry CH3CN
(30 mL) under argon was cooled to ꢁ40 ꢀC, and then N-tert-
butyloxycarbonyl-ethanolamine (6, 2.43 mL, 1.4 mmol) in
dry CH3CN (20 mL) was added dropwise for over 12 min.
TLC indicated a new product and a trace of 7. Dry pyridine
(6.5 mL) was then added, and the mixture was allowed to
warm to room temperature. The solvent volume was reduced
to ca. 20 mL, EtOAc (50 mL) was added, the resulting precip-
itate was filtered off, and the filtrate was concentrated to a resid-
ual oil (7). The oil was then cooled with an ice-water bath and
diluted with CH3CN (50 mL). RuCl3$H2O (3 mg, 0.03 mmol)
and NaIO4 (0.50 g, 0.8 mmol) were added followed by water
(75 mL). The resulting orange mixture was stirred at room tem-
perature for 1 h. The mixture was then diluted with ether
3.4. [1,2,3]Oxathiadiazolidin-2,2-dioxide (3g)
Sulfamidate 8 (0.5 g, 2.2 mmol) was dissolved in CH2Cl2
(20 mL), and TFA (0.86 mL, 5 equiv) was added. The mixture
was stirred for 30 min and then the solvent evaporated under re-
duced pressure. The residual oil was treated with Et3N (typically
<5 drops), until the mixture tested basic. The mixture was then
filtered through a plug of silica using CH2Cl2/MeOH ¼
20:1 to give 82% yield of 3g as a yellow oil. 1H NMR
(CDCl3): d 1.53 (s, 9H), 3.40e3.44 (t, 2H, J ¼ 12.8 Hz),
Table 1
In vitro antibacterial activity (MIC, mg/mL) of the carbapenem derivatives (IIIaei)
Strains
IIIa
IIIb
IIIc
IIId
IIIe
3.12
IIIf
3.12
IIIg
3.12
IIIh
IIIi
6.25
IPMa
1.560
MPMb
Staphylococcus aureus 1218
Coagulase negative staphylococci
Enterococcus faecalis 2347
Streptococcus pyogenes 9889
Streptococcus agalactiae 32
Streptococcus pneumoniae 0025
Haemophilus influenzae 1210
Escherichia coli 04
12.5
25.0
25.0
3.12
6.25
6.250
0.098
12.50
0.013
0.049
0.01
0.098
6.25
0.198
0.391
25.0
0.04
0.098
6.25
0.01
0.098
6.25
0.01
0.098
3.12
0.02
0.098
6.25
0.02
0.098
6.25
0.01
0.049
3.12
0.025
1.563
<0.01
0.01
6.25
0.02
0.02
0.02
<0.01
<0.01
0.01
0.04
0.04
0.04
0.04
0.02
0.02
0.02
0.02
0.02
0.025
0.02
0.013
6.25
0.01
0.02
0.02
6.25
<0.01
6.250
0.195
0.781
0.391
0.781
0.781
12.500
3.125
12.50
0.098
0.198
0.098
0.098
0.198
25.0
12.5
6.25
6.25
12.5
6.25
3.12
3.125
0.049
0.025
0.025
0.025
0.049
12.5
0.049
0.098
0.049
0.049
0.098
0.198
0.198
0.198
0.195
0.195
0.049
0.049
0.049
0.098
0.049
0.049
0.049
0.049
0.049
0.049
0.195
0.781
0.781
0.781
6.25
0.049
0.098
0.195
0.098
0.198
0.049
0.049
0.049
0.049
0.198
6.25
0.025
0.025
0.025
0.025
0.049
3.12
Klebsiella pneumoniae 523
Citrobacter freundii 323
Enterobacter cloacae 34
Serratia marcescens 3349
Acinetobacter baumannii 2289
Pseudomonas aeruginosa 5455
12.5
3.125
25.0
25.0
12.5
3.125
12.5
0.781
50.0
100.0
12.5
12.5
12.5
1.563
1.563
1.563
a
Imipenem.
Meropenem.
b

1180
S.J. Kim et al. / European Journal of Medicinal Chemistry 42 (2007) 1176e1183
Table 2
Comparative in vitro antibacterial activity of IIIi, meropenem and imipenem against 40 strains (MIC, mg/mL)
Organism
IIIi
IPM
MPM
Organism
IIIi
IPM
0.10
MPM
Staphylococcus aureus giorgio
Staphylococcus aureus 209P
Staphylococcus aureus 503
Micrococcus luteus ATCC 9341
Streptococcus faecium 77A
Streptococcus agalactiae B
Streptococcus durans D
0.05
0.02
0.10
0.10
0.05
0.05
0.01
0.05
0.80
0.05
0.05
0.40
0.80
0.40
0.20
0.40
0.05
0.02
0.05
0.01
0.02
0.02
Salmonella paratyphi A
Salmonella typhimurium
Salmonella oranienburg
Salmonella typhi
0.05
0.10
0.10
0.03
0.10
0.10
0.05
0.01
0.02
0.10
0.20
0.40
0.20
0.20
0.40
0.40
0.40
0.05
0.01
0.01
0.02
0.05
0.05
0.01
0.10
0.02
0.05
0.01
0.01
0.05
0.05
0.20
0.10
0.10
0.10
0.10
0.05
0.05
0.05
0.02
0.02
0.01
0.02
<0.01
0.02
0.10
0.03
0.05
1.60
1.60
0.80
0.40
0.40
0.02
0.02
0.02
0.05
0.01
0.02
0.01
<0.01
0.01
<0.01
0.01
0.10
0.03
0.03
0.80
0.80
0.80
0.80
0.80
0.10
0.10
0.10
0.05
0.20
0.10
0.40
0.40
0.05
0.20
0.20
0.20
0.10
0.10
0.20
0.40
0.80
0.20
0.10
0.10
0.20
0.20
<0.01
0.01
<0.01
Salmonella orion
Salmonella give
Klebsiella pneumoniae 477
Enterobacter cloacae
Enterobacter cloacae 417
Serratia marcescens 370
Serratia marcescens 6093
Serratia marcescens 14273
Proteus mirabilis 112/3
Proteus mirabilis 174/3
Proteus vulgaris 868
Bacillus subtilis ATCC 6633
Bacillus megatherium
Pseudomonas aeruginosa 9027
Pseudomonas aeruginosa 77/2
Pseudomonas aeruginosa 110/2
Pseudomonas aeruginosa 880/2
Pseudomonas cepacia
Escherichia coli 086
Escherichia coli 0114
Escherichia coli 0126
Proteus rettgeri 936
Proteus rettgeri 937
Escherichia coli V6311/65
Escherichia coli TEM
Escherichia coli 1507
Pasteurella multocida
Corynebacterium diphtheriae
Corynebacterium pyogenes
3.79e3.84 (t, 2H, J ¼ 12.7 Hz), 4.91 (s, 1H). 13C NMR
(CDCl3): d 29.06, 43.89, 46.32, 83.78, 163.28.
3.7. (2S,4S )-2-(5-Methyl-1,1-dioxo-
[1,2,5]thiadiazolidin-2-ylmethyl)-4-
tritylthio-1-(allyloxycarbonyl)
pyrrolidine (12a)
3.5. (2S,4S )-2-Hydroxymethyl-4-tritylthio-
1-(allyloxycarbonyl)pyrrolidine (10)
To a stirred solution of 3a (0.30 g, 2.1 mmol) in dry DMF
(10 mL) was added dropwise sodium hydride (0.10 g,
2.3 mmol, 60% oil suspension) at 0 ꢀC and was stirred for
1 h at room temperature. To the resulting solution was added
11 (1.0 g, 1.9 mmol) solution in dry DMF (5 mL) at 0 ꢀC
and was stirred for 4 h at room temperature. The reaction mix-
ture was poured into cold dilute HCl and extracted with ethyl
acetate. The organic layer was successively washed with water
and dried over anhydrous Na2SO4. Evaporation of the solvent
in vacuo gave a crude residue, which was purified by silica gel
column chromatography (EtOAc/n-hexane ¼ 1:6) to give 12a
(0.67 g, 62%) as a pale yellow oil. 1H NMR (CDCl3):
d 1.79e1.89 (m, 2H), 2.11e2.23 (m, 2H), 2.70 (s, 3H),
3.24e3.41 (m, 5H), 3.43e3.45 (d, 2H, J ¼ 5.6 Hz), 3.77 (bs,
1H), 4.42e4.45 (m, 2H), 5.18e5.28 (m, 2H), 5.83e5.85 (m,
1H), 7.18e7.30 (m, 9H), 7.43e7.46 (d, 6H, J ¼ 7.4 Hz). 13C
NMR (CDCl3): d 31.39, 32.83, 33.87, 36.81, 39.64, 46.94,
50.20, 55.78, 67.21, 111.27, 126.82, 128.02, 129.44, 132.66,
144.61, 162.58.
To a solution of 9 (107.3 g, 0.22 mol) in THF (800 mL) was
added slowly LiBH4 (4.8 g, 0.22 mol) at 0 ꢀC and was stirred for
9 h at room temperature. The mixture was diluted with H2O
(200 mL), 1 N HCl (200 mL) and ethyl acetate (800 mL). The
organic layer was dried over anhydrous Na2SO4, concentrated,
and the resulting residue was purified by silica gel column chro-
matography (EtOAc/n-hexane ¼ 1:3) to give 10 (79.4 g, 78%)
1
as a pale yellow oil. H NMR (CDCl3): d 1.58 (m, 1H), 1.98
(m, 1H), 2.75e2.89 (m, 2H), 3.01 (m, 1H), 3.55 (bs, 2H), 3.74
(m, 1H), 4.52 (bs, 2H), 5.23e5.30 (m, 2H), 5.80e5.88 (m,
1H), 7.20e7.27 (m, 9H), 7.47 (d, 6H, J ¼ 7.5 Hz).
3.6. (2S,4S )-2-Mesyloxymethyl-4-tritylthio-
1-(allyloxycarbonyl)pyrrolidine (11)
A solution of 10 (68.9 g, 0.15 mol) and triethylamine
(24.2 mL, 0.18 mol) in dry CH2Cl2 (400 mL) was cooled to
0 ꢀC under nitrogen and treated with methanesulfonyl chloride
(20.6 g, 0.18 mol). The mixture was stirred at 0 ꢀC for 1 h, di-
luted with CH2Cl2 (200 mL), and washed with 10% NaHCO3
and brine. The organic layer was dried over anhydrous
Na2SO4. Evaporation of the solvent in vacuo gave a crude res-
idue, which was purified by silica gel column chromatography
(EtOAc/n-hexane ¼ 1:3) to give 11 (75.2 g, 93%) as a pale
yellow oil. 1H NMR (CDCl3): d 1.81 (bs, 1H), 2.11 (bs,
1H), 2.75e2.82 (bs, 2H), 2.99 (bs, 4H), 3.95 (bs, 1H), 4.22
(bs, 1H), 4.40e4.50 (bs, 3H), 5.22e5.31 (bs, 2H), 5.80e
5.91 (m, 1H), 7.20e7.31 (m, 9H), 7.48 (d, 6H, J ¼ 7.7 Hz).
The syntheses of compounds 12bei were carried out by the
same procedure as described for the preparation of 12a.
1
12b: Yield 69%. H NMR (CDCl3): d 1.13 (s, 3H), 1.83e
1.86 (m, 2H), 2.01e2.12 (m, 2H), 2.92 (m, 2H), 3.25e3.41
(m, 5H), 3.42e3.45 (d, 2H, J ¼ 6.3 Hz), 3.70 (bs, 1H), 4.41e
4.44 (m, 2H), 5.19e5.28 (m, 2H), 5.83e5.86 (m, 1H), 7.18e
7.28 (m, 9H), 7.43e7.47 (d, 6H, J ¼ 7.5 Hz). 13C NMR
(CDCl3): d 14.19, 33.32, 38.56, 40.96, 44.83, 46.45, 46.94,
52.20, 57.79, 66.81, 112.27, 125.62, 129.03, 129.44, 133.66,
144.21, 162.48.

S.J. Kim et al. / European Journal of Medicinal Chemistry 42 (2007) 1176e1183
1181
1
12c: Yield 60%. H NMR (CDCl3): d 1.56 (s, 3H), 1.83e
1.85 (bs, 1H), 2.69e2.79 (m, 2H), 3.07e3.22 (m, 3H),
3.52e3.54 (m, 2H), 3.70e3.74 (m, 3H), 4.13 (bs, 1H), 4.45
(bs, 1H), 5.19e5.29 (m, 3H), 5.85 (m, 1H), 7.26e7.30 (m,
9H), 7.44e7.46 (d, 6H, J ¼ 7.9 Hz). 13C NMR (CDCl3):
d 15.19, 34.42, 39.66, 44.83, 46.45, 46.94, 52.20, 55.24,
56.79, 66.85, 114.37, 125.32, 129.43, 129.44, 133.10,
150.21, 162.48.
3.8. Allyl(1R,5S,6S )-6-[(1R)-hydroxyethyl]-2-[5-(5-
methyl-1,1-dioxo-[1,2,5]thiadia-zolidin-2-ylmethyl)]-1-
(allyloxycarbonyl)pyrrolidin-3-ylthio]-1-
methylcarbapen-2-em-3-carboxylate (IIa)
To a solution of 12a (0.60 g, 1.0 mmol) in CH2Cl2 (2 mL)
was added dropwise triethylsilane (0.13 g, 1.1 mmol) at 5 ꢀC,
and then TFA (2 mL). After stirring for 30 min at room tem-
perature, the mixture was evaporated under reduced pressure.
The residue was dissolved with ethyl acetate and washed
with 10% NaHCO3 and brine. The organic layer was concen-
trated in vacuo to give a residue (Ia), which was used without
further purification. A solution of 13 (0.40 g, 0.80 mmol) in
CH3CN (10 mL) was cooled to 0 ꢀC under N2. To this solution
was added diisopropylethylamine (0.13 g, 1.0 mmol) and a so-
lution of the mercapto compound Ia in CH3CN (5 mL). After
stirring for 5 h, the mixture was diluted with ethyl acetate,
washed with 10% NaHCO3, brine, and dried over anhydrous
MgSO4. Evaporation in vacuo gave a foam, which was purified
by silica gel chromatography (EtOAc/n-hexane ¼ 3:1) to give
IIa (0.16 g, 34%) as a yellow amorphous solid. 1H NMR
(CDCl3): d 1.25e1.28 (d, 3H, J ¼ 5.4 Hz), 1.34e1.36 (d, 3H,
J ¼ 4.6 Hz), 2.09e2.02 (m, 2H), 2.53 (bs, 2H), 2.75 (s, 3H),
3.23e3.30 (m, 5H), 3.45 (bs, 1H), 3.95e4.18 (m, 2H), 4.21e
4.25 (m, 2H), 4.59e4.67 (m, 4H), 4.69 (dd, 1H, J ¼ 5.4 and
13.8 Hz), 4.83 (dd, 1H, J ¼ 5.7 and 14.1 Hz), 5.23e5.33 (m,
4H), 5.42 and 5.47 (2 s, 1H), 5.90e6.01 (m, 2H).
1
12d: Yield 66%. H NMR (CDCl3): d 1.26 (s, 6H), 1.86e
1.89 (bs, 1H), 2.70e2.72 (m, 3H), 2.95e3.14 (m, 4H), 3.77
(bs, 2H), 4.09e4.11 (m, 1H), 4.44e4.47 (m, 2H), 5.25e5.30
(m, 2H), 5.84e5.87 (m, 1H), 7.22e7.34 (m, 9H), 7.44e7.46
(d, 6H, J ¼ 7.4 Hz). 13C NMR (CDCl3): d 24.40, 35.42,
40.96, 46.32, 48.20, 49.92, 52.10, 56.91, 59.11, 66.89,
116.21, 126.28, 128.20, 129.17, 132.98, 153.03, 163.23.
1
12e: Yield 62%. H NMR (CDCl3): d 1.28 (s, 9H), 1.97e
2.01 (m, 1H), 2.62e2.63 (d, 2H, J ¼ 3.0 Hz), 2.72e2.75 (m,
2H), 3.21e3.32 (m, 2H), 3.44e3.47 (m, 2H), 3.82e3.84 (bs,
1H), 4.10e4.19 (m, 2H), 4.45e4.47 (m, 2H), 5.19e5.25 (m,
2H), 5.81e5.88 (m, 1H), 7.21e7.31 (m, 9H), 7.43e7.46 (d,
6H, J ¼ 7.1 Hz). 13C NMR (CDCl3): d 29.98, 41.36, 42.42,
44.12, 46.97, 49.81, 52.32, 55.54, 68.54, 81.34, 116.11,
126.12, 128.89, 129.76, 133.10, 149.99, 152.11, 162.50,
169.11.
1
12f: Yield 68%. H NMR (CDCl3): d 1.60e1.62 (m, 1H),
2.69e2.72 (m, 2H), 3.11e3.18 (m, 4H), 3.26e3.28 (m, 2H),
3.33e3.34 (d, 2H, J ¼ 1.6 Hz), 3.78 (bs, 1H), 4.13e4.18 (m,
2H), 4.44e4.49 (m, 2H), 5.18e5.24 (m, 2H), 5.79e5.88 (m,
1H), 7.19e7.36 (m, 14H), 7.44e7.47 (d, 6H, J ¼ 8.6 Hz).
13C NMR (CDCl3): d 40.96, 45.18, 46.95, 48.20, 49.79,
54.25, 59.45, 68.85, 117.32, 124.32, 126.22, 127.39, 127.72,
128.98, 129.76, 133.72, 144.61, 163.24.
The syntheses of compounds IIbei were carried out by the
same procedure as described for the preparation of IIa.
1
IIb: Yield 54%. H NMR (CDCl3): d 1.22e1.29 (m, 9H),
1.96e2.10 (m, 2H), 2.17e2.45 (m, 2H), 3.09 (bs, 2H), 3.30e
3.39 (m, 3H), 3.66e3.80 (m, 2H), 4.02e4.05 (m, 3H), 4.25e
4.27 (m, 2H), 4.56e4.60 (m, 4H), 4.66 (dd, 1H, J ¼ 5.3 and
11.2 Hz), 4.81 (dd, 1H, J ¼ 5.7 and 12.2 Hz), 5.21e5.24 (m,
4H), 5.42 and 5.45 (2 s, 1H), 5.90e6.01 (m, 2H).
1
12g: Yield 61%. H NMR (CDCl3): d 1.70e188 (m, 1H),
1.98e2.10 (m, 1H), 2.68e2.77 (m, 2H), 2.90e2.96 (t, 2H,
J ¼ 7.4 Hz), 3.28e3.30 (m, 2H), 3.61e3.67 (m, 2H), 3.75e
3.80 (m, 2H), 4.47e4.53 (bs, 2H), 5.20e5.28 (m, 2H),
5.81e5.90 (m, 1H), 7.19e7.29 (m, 9H), 7.44e7.46 (d, 6H,
J ¼ 7.4 Hz). 13C NMR (CDCl3): d 36.81, 39.49, 49.21,
50.86, 52.86, 57.92, 62.29, 67.92, 111.29, 127.01, 128.23,
129.83, 133.03, 158.83, 169.32.
1
IIc: Yield 57%. H NMR (CDCl3): d 1.27e1.29 (d, 2H,
J ¼ 4.1 Hz), 1.31e1.33 (d, 2H, J ¼ 6.3 Hz), 1.58 (s, 3H),
2.65e2.67 (m, 3H), 3.12e3.27 (m, 2H), 3.36e3.49 (m, 2H),
3.51e3.62 (m, 3H), 3.69e3.77 (m, 2H), 3.90e4.08 (m, 3H),
4.44e4.60 (bs, 5H), 4.62 (dd, 1H, J ¼ 6.2 and 10.2 Hz), 4.79
(dd, 1H, J ¼ 5.2 and 10.2 Hz), 5.26e5.30 (m, 4H), 5.42 and
5.45 (2 s, 1H), 5.90e6.01 (m, 2H).
1
12h: Yield 57%. H NMR (CDCl3): d 1.44 (s, 9H), 1.64e
1.68 (m, 2H), 1.85e1.87 (m, 1H), 2.63e2.70 (m, 2H),
3.08e3.14 (q, 2H), 3.26e3.31 (m, 2H), 3.47e3.76 (m, 2H),
3.99e4.11 (m, 3H), 4.44 (bs, 2H), 5.18e5.22 (m, 2H),
5.80e5.86 (m, 1H), 7.21e7.31 (m, 9H), 7.43e7.46 (d, 6H,
J ¼ 7.7 Hz). 13C NMR (CDCl3): d 27.76, 29.98, 37.23,
41.59, 43.99, 48.31, 49.84, 53.36, 56.92, 67.94, 68.76,
81.92, 116.73, 126.12, 127.91, 129.59, 133.10, 153.28,
163.26, 176.01.
1
IId: Yield 56%. H NMR (CDCl3): d 1.27e1.28 (d, 3H,
J ¼ 2.92 Hz), 1.31e1.32 (d, 3H, J ¼ 6.3 Hz), 1.59 (s, 6H),
2.09e2.12 (m, 1H), 2.63e2.66 (m, 2H), 2.91e2.99 (m, 2H),
3.23e3.25 (m, 4H), 4.13e4.15 (m, 5H), 4.51e4.61 (bs, 4H),
4.71 (dd, 1H, J ¼ 3.9 and 7.2 Hz), 4.80 (dd, 1H, J ¼ 4.3 and
10.2 Hz), 5.24e5.33 (m, 4H), 5.93e6.96 (m, 2H).
1
IIe: Yield 45%. H NMR (CDCl3): d 1.26e1.28 (d, 3H,
1
12i: Yield 55%. H NMR (CDCl3): d 1.81e1.85 (m, 2H),
J ¼ 7.2 Hz), 1.35e1.38 (d, 3H, J ¼ 6.2 Hz), 2.07e2.13 (m,
1H), 2.59 (bs, 2H), 2.76e2.83 (m, 2H), 3.25e3.49 (m, 3H),
3.50e3.74 (m, 3H), 3.89 (m, 1H), 4.08e4.15 (m, 2H), 4.22e
4.24 (m, 1H), 4.59e4.66 (m, 4H), 4.67 (dd, 1H, J ¼ 5.2 and
10.8 Hz), 4.80 (dd, 1H, J ¼ 5.7 and 11.1 Hz), 5.21e5.24 (m,
4H), 5.42 and 5.47 (2 s, 1H), 5.87e6.00 (m, 2H).
2.25e2.26 (bs, 1H), 2.73 (s, 3H), 2.75e2.79 (m, 2H), 2.80e
2.81 (bs, 2H), 3.25e3.30 (m, 2H), 3.43e3.50 (m, 4H), 3.72
(bs, 1H), 4.43e4.45 (m, 2H), 5.18e5.21 (m, 2H), 5.84e5.85
(m, 1H), 7.20e7.39 (m, 9H), 7.44e7.46 (d, 6H, J ¼ 7.7 Hz).
13C NMR (CDCl3): d 27.24, 36.08, 41.10, 42.94, 45.37,
49.33, 54.24, 58.45, 64.24, 66.85, 67.75, 116.38, 126.28,
128.52, 129.87, 133.11, 153.43, 163.50.
1
IIf: Yield 43%. H NMR (CDCl3): d 1.26e1.28 (d, 3H,
J ¼ 7.2 Hz), 1.35e1.37 (d, 2H, J ¼ 6.2 Hz), 2.04e2.11 (m,

1182
S.J. Kim et al. / European Journal of Medicinal Chemistry 42 (2007) 1176e1183
2H), 2.45e2.51 (m, 2H), 3.16e3.20 (m, 2H), 3.23e3.39 (m,
4H), 3.35 (m, 1H), 3.54 (bs, 1H), 4.08e4.26 (m, 5H), 4.60e
4.64 (m, 4H), 4.71 (dd, 1H, J ¼ 5.5 and 7.8 Hz), 4.81 (dd,
1H, J ¼ 2.6 and 8.1 Hz), 5.22e5.30 (m, 4H), 5.42 and 5.47
(2 s, 1H), 5.90e5.99 (m, 2H), 7.30e7.37 (m, 5H).
cmꢁ1. HRMS(FAB) Calcd. for C19H30N4O6S2 474.1607,
found 474.1607.
IIIc: Yield 19%. UV lmax: 298 nm. 1H NMR (D2O):
d
1.11e1.12 (d, 3H, J ¼ 6.3 Hz), 1.13e1.15 (d, 3H,
J ¼ 6.7 Hz), 1.17 (s, 3H), 1.50e1.53 (bs, 1H), 2.51e2.53
(m, 2H), 2.76 (q, 2H), 3.06e3.08 (m, 2H), 3.46e3.62 (m,
6H), 3.71e3.73 (dd, 2H, J ¼ 5.4 and 6.8 Hz), 3.93e3.99 (m,
2H), 4.05e4.10 (m, 2H). IR (KBr): 3430, 3260, 1710, 1660,
1340 (S]O) cmꢁ1. HRMS(FAB) Calcd. for C18H28N4O6S2
460.1450, found 460.1452.
1
IIg: Yield 54%. H NMR (CDCl3): d 1.14e1.17 (bs, 3H),
1.35e1.37 (d, 3H, J ¼ 6.1 Hz), 1.66e1.71 (m, 2H), 2.00e2.04
(m, 2H), 3.28e3.35 (m, 4H), 3.67 (bs, 1H), 3.97e4.11 (m,
3H), 4.13e4.23 (m, 2H), 4.51e4.60 (m, 4H), 4.67 (dd, 1H,
J ¼ 5.6 and 9.8 Hz), 4.84 (dd, 1H, J ¼ 5.4 and 10.3 Hz),
5.23e5.33 (m, 4H), 5.42 and 5.47 (2 s, 1H), 5.89e6.02 (m, 2H).
IIId: Yield 17%. UV lmax: 298 nm. 1H NMR (D2O):
1
IIh: Yield 45%. H NMR (CDCl3): d 1.23e1.26 (d, 3H,
d
1.09e1.10 (d, 3H, J ¼ 6.9 Hz), 1.13e1.14 (d, 3H,
J ¼ 7.1 Hz), 1.32e1.35 (d, 3H, J ¼ 7.2 Hz), 1.64e1.67 (m,
2H), 2.17e2.23 (m, 2H), 2.59 (bs, 2H), 3.25e3.49 (m, 6H),
3.69e3.74 (m, 1H), 3.99 (bs, 2H), 4.08e4.15 (m, 2H),
4.22e4.24 (m, 1H), 4.59e4.66 (m, 4H), 4.67 (dd, 1H,
J ¼ 5.2 and 10.8 Hz), 4.80 (dd, 1H, J ¼ 5.7 and 11.1 Hz),
5.21e5.24 (m, 4H), 5.87e6.00 (m, 2H).
J ¼ 7.4 Hz), 1.29 (s, 6H), 1.62e1.65 (m, 2H), 2.10e2.12 (m,
2H), 2.64e2.67 (m, 1H), 3.24e3.35 (m, 8H), 3.54e3.56 (m,
1H), 3.83e3.90 (m, 2H), 4.04e4.11 (m, 2H). IR (KBr):
3470, 3280, 1720, 1680, 1310 (S]O) cmꢁ1. HRMS(FAB)
Calcd. for C19H30N4O6S2 474.1607, found 474.1609.
IIIe: Yield 20%. UV lmax: 298 nm. 1H NMR (D2O): d 1.15e
1.18 (d, 3H, J ¼ 6.6 Hz), 1.20e1.23 (d, 3H, J ¼ 7.0 Hz), 1.67e
1.83 (m, 3H), 2.32e2.37 (m, 1H), 2.60e2.69 (m, 2H), 3.27e
3.30 (m, 1H), 3.39e3.43 (m, 7H), 3.52e3.55 (m, 2H), 3.76e
3.87 (m, 2H), 4.06e4.15 (m, 2H). IR (KBr): 3490, 3280,
1710, 1670, 1310 (S]O) cmꢁ1. HRMS(FAB) Calcd. for
C17H26N4O6S2 446.1294, found 446.1299.
1
IIi: Yield 49%. H NMR (CDCl3): d 1.19e1.21 (m, 3H),
1.26e1.28 (m, 3H), 1.35e1.36 (d, 3H, J ¼ 6.2 Hz), 1.74e
1.76 (m, 2H), 2.52e2.54 (bs, 2H), 2.76 (s, 3H), 3.23e3.29
(m, 3H), 3.49e3.50 (m, 2H), 3.59 (bs, 1H), 4.01e4.09 (m,
2H), 4.21e4.24 (m, 2H), 4.57e4.59 (m, 4H), 4.67 (dd, 1H,
J ¼ 6.6 and 9.0 Hz), 4.81 (dd, 1H, J ¼ 5.4 and 11.2 Hz),
5.23e5.36 (m, 4H), 5.84e6.02 (m, 2H).
IIIf: Yield 16%. UV lmax: 298 nm. 1H NMR (D2O): d 1.05e
1.08 (d, 3H, J ¼ 7.0 Hz), 1.11e1.12 (d, 3H, J ¼ 6.7 Hz), 1.56e
1.66 (m, 1H), 2.07 (bs, 2H), 2.58e2.63 (m, 2H), 3.01e3.02 (m,
1H), 3.01e3.33 (m, 9H), 3.35e3.37 (m, 2H), 3.52e3.54 (m,
2H), 4.01e4.06 (m, 2H), 7.27e7.30 (m, 5H). IR (KBr): 3400,
3360, 1710, 1680, 1325 (S]O) cmꢁ1. HRMS(FAB) Calcd.
for C24H32N4O6S2 536.1763, found 536.1770.
3.9. (1R,5S,6S )-6-[(1R)-Hydroxyethyl]-2-[5-(5-methyl-
1,1-dioxo-[1,2,5]thiadiazolidin-2-ylmethyl)]-
1-(allyloxycarbonyl)pyrrolidin-3-ylthio]-1-
methylcarbapen-2-em-3-carboxylic acid (IIIa)
To a stirred solution of IIa (80 mg, 0.13 mol) and
Pd(PPh3)4 (10 mg) in CH2Cl2 (5 mL) was added dropwise n-
tributyltin hydride (0.12 mL, 0.22 mmol) at 0 ꢀC and was
stirred for 1 h at same temperature. The resulting solution
was diluted with water (10 mL) and the organic layers were
washed with water (2 ꢂ 10 mL). The combined aqueous layers
were washed with ethyl ether (2 ꢂ 10 mL) and lyophilized to
give a yellow powder which was purified on a Diaion HP-20
column, eluting with 2% THF in water. Fractions having UV
absorption at 298 nm were collected and lyophilized again
to give the title compound IIIa as an amorphous solid. Yield
18%. UV lmax: 298 nm. 1H NMR (D2O): d 1.09 (d, 3H,
J ¼ 6.4 Hz), 1.18e1.21 (d, 3H, J ¼ 6.9 Hz), 1.50e1.57 (m,
1H), 2.11 (m, 2H), 2.55e2.59 (m, 2H), 2.64 (s, 3H), 3.16e
3.19 (m, 1H), 3.26e3.35 (m, 7H), 3.45e3.48 (m, 2H),
3.71e3.87 (m, 2H), 4.09e4.16 (m, 2H). IR (KBr): 3400,
3250, 1710, 1680, 1325 (S]O) cmꢁ1. HRMS(FAB) Calcd.
for C18H28N4O6S2 460.1450, found 460.1455.
The syntheses of compounds IIIbei were carried out by the
same procedure as described for the preparation of IIIa.
IIIb: Yield 16%. UV lmax: 298 nm. 1H NMR (D2O): d 1.11
(s, 3H), 1.13e1.14 (d, 3H, J ¼ 5.8 Hz), 1.17e1.20 (d, 3H,
J ¼ 6.3 Hz), 1.64e1.66 (m, 1H), 2.13 (bs, 2H), 2.68e2.70
(m, 2H), 3.03e3.07 (m, 2H), 3.25e3.42 (m, 6H), 3.44e3.59
(m, 2H), 3.57e3.62 (m, 2H), 3.57e3.59 (m, 2H), 4.15e4.17
(m, 2H). IR (KBr): 3450, 3300, 1720, 1670, 1355 (S]O)
IIIg: Yield 18.3%. UV lmax: 298 nm. 1H NMR (D2O):
d
1.08e1.11 (d, 3H, J ¼ 5.4 Hz), 1.15e1.16 (d, 3H
J ¼ 6.7 Hz), 1.18e1.20 (s, 1H), 1.21e1.22 (m, 2H), 2.72e
2.82 (m, 2H), 3.07e3.09 (m, 5H), 3.27e3.40 (m, 2H), 3.73
(dd, 2H, J ¼ 2.4 and 5.3 Hz), 4.05e4.16 (m, 5H). IR (KBr):
3440, 3220, 1710, 1670, 1370 (S]O) cmꢁ1. HRMS(FAB)
Calcd. for C17H25N3O7S2 447.1134, found 447.1134.
IIIh: Yield 15%. UV lmax: 298 nm. 1H NMR (D2O): d 1.12e
1.14 (d, 3H, J ¼ 7.2 Hz), 1.19e1.21 (d, 3H, J ¼ 6.3 Hz), 1.57e
1.68 (m, 4H), 2.58e2.68 (m, 3H), 3.24e3.46 (m, 9H), 3.53e
3.58 (m, 2H), 3.85 (bs, 2H), 4.12e4.14 (m, 2H). IR (KBr):
3470, 3330, 1710, 1680, 1340 (S]O) cmꢁ1. HRMS(FAB)
Calcd. for C18H28N4O6S2 460.1450, found 460.1453.
IIIi: Yield 15%. UV lmax: 298 nm. 1H NMR (D2O):
1.09e1.11 (d, 3H, J ¼ 7.2 Hz), 1.16e1.18 (d, 3H,
d
J ¼ 6.3 Hz), 1.59e1.62 (m, 1H), 1.77e1.79 (m, 2H), 2.10e
2.11 (bs, 1H), 2.62e2.64 (m, 2H), 2.68 (s, 3H), 3.27e3.34
(m, 4H), 3.36e3.39 (m, 4H), 3.55e3.59 (m, 2H), 3.83e3.85
(bs, 1H), 3.91e3.93 (bs, 1H), 4.10e4.15 (m, 3H). IR (KBr):
3420, 3290, 1720, 1680, 1390 (S]O) cmꢁ1. HRMS(FAB)
Calcd. for C19H30N4O6S2 474.1607, found 474.1610.
Acknowledgements
We would like to thank Hawon Pharmaceuticals Co. which
supported us with fund.

S.J. Kim et al. / European Journal of Medicinal Chemistry 42 (2007) 1176e1183
1183
[6] K. Inoue, Y. Hamana, T. Inoue, M. Fukasawa, M. Kato, Abstracts of Pa-
pers of 34th Interscience Conference on Antimicrobial Agents and Che-
motherapy, No. 1, Orlando, 1994.
References
[1] W. Leanza, K. Wildonger, T.W. Miller, B.G. Christensen, J. Med. Chem.
22 (1979) 1435.
[7] N. Sato, F. Ohba, Drugs Future 21 (1996) 361e365.
[8] C.-H. Oh, J.-H. Cho, J. Antibiot. 47 (1994) 126e128.
[9] C.B. Jin, I.S. Jung, H.-J. Ku, J.W. Yook, D.-H. Kim, J.-H. Cho,
M.S. Kim, C.-H. Oh, Toxicology 138 (1999) 59e67.
[2] J. Birnbaum, F.M. Kahan, J.S. MacDonald, Am. J. Med. 78 (Suppl. 6A)
(1985) 3e21.
[3] M. Sunagawa, H. Matsumure, T. Inoue, M. Fukasawa, M. Kato, J. Anti-
biot. 43 (1990) 519e532.
[10] C.-H. Oh, H.-W. Cho, I.-K. Lee, J.-Y. Gong, J.-H. Choi, J.-H. Cho, Arch.
Pharm. Pharm. Med. Chem. 335 (2002) 152e158.
[4] C.J. Gill, J.J. Jackson, L.S. Gerckens, B.A. Pelak, R.K. Thompson,
J.G. Sundelof, H. Kropp, H. Rosen, Antimicrob. Agents Chemother. 42
(1998) 1996e2001.
[11] C.-H. Oh, H.-W. Cho, J.-H. Cho, Eur. J. Med. Chem. 37 (2002) 743e
754.
[12] C.-H. Oh, J.-H. Cho, Eur. J. Med. Chem. 41 (2006) 50e55.
[13] D.H. Shih, F.L. Baker, B.G. Christensen, Heterocycles 21 (1984) 29e40.
[5] Y. Iso, T. Irie, Y. Nishino, K. Motokawa, Y. Nishitani, J. Antibiot. 49
(1996) 199e209.