Synthesis and antibacterial evaluation of 1β-methyl-2-[5-(1-methoxyimino-2-substituted sulfonamide ethyl)pyrrolidin-3-ylthio]carbapenems and their related compounds

Article abstract of DOI:10.1016/j.ejmech.2006.10.006

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

Full text of DOI:10.1016/j.ejmech.2006.10.006

European Journal of Medicinal Chemistry 42 (2007) 358e364
http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antibacterial evaluation
of 1b-methyl-2-[5-(1-methoxyimino-2-substituted sulfonamide
ethyl)pyrrolidin-3-ylthio]carbapenems and their related compounds
Heechol Jeon b, Nam Hyun Jo a, Kyung Ho Yoo a, Joung-Hoon Choi b,
Heeyeong Cho c, Jung-Hyuck Cho a, Chang-Hyun Oh a,
*
a Medicinal Chemistry Research Center, Korea Institute of Science and Technology, 39-1 Awolgok-dong, Seongbuk-gu,
Seoul 130-650, Republic of Korea
b Department of Chemistry, Hanyang University, Seoul 133-791, Republic of Korea
c Pharmaceutical Screening Lab, Korea Research Institute of Chemical Technology, Taejon 305-600, Republic of Korea
Received 26 July 2006; received in revised form 9 October 2006; accepted 12 October 2006
Available online 6 December 2006
Abstract
The synthesis of a new series of 1b-methylcarbapenems having methoxyimine and substituted sulfonamide moieties is described. Their in
vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituents on the pyrro-
lidine ring was investigated. A particular compound (IIIc) having methylaminosulfonamide moiety showed the most potent antibacterial
activity.
Ó 2006 Elsevier Masson SAS. All rights reserved.
Keywords: 1b-Methylcarbapenems; Antibacterial activity; DHP-I stability
1. Introduction
At present, several carbapenem derivatives such as S-4661 (3)
[8], BO-2727 [9] and E-1010 [10] are under clinical or preclin-
ical studies since the launch of meropenem.
Carbapenems are one of the most potent types of antibacte-
rial agents and are among those used as last resort against in-
fections in the clinical field. Three carbapenems, imipenem
[1e2], meropenem (1) [3], and ertapenem(2) [4] have been
marketed so far. In particular, it was revealed that 1b-methyl-
carbapenems showed not only a broad antibacterial spectrum
against both Gram-positive and Gram-negative bacteria but
also high stability to human renal DHP-I [5e6]. The carbape-
nem compounds which have a (3S )-pyrrolidin-3-ylthio group
at the C-2 position in the carbapenem skeleton are noted for
their broad and potent antibacterial activity [7] and a large
number of derivatives have been synthesized and investigated.
We were also reported that the carbapenem compounds
having a pyrrolidin-3-ylthio group at the C-2 position in the
carbapenem skeleton are noted for their broad and potent an-
tibacterial activity, and a large number of derivatives have
been synthesized [11e14]. We conceived that the introduction
of additional methoxyimine and sulfonamide moieties into
pyrrolidine side chain was responsible for the improvements
of antibacterial activity, because the compounds having me-
thoxyimine and sulfonamide moieties have shown to enhance
drug activity in general. In this paper, we described the syn-
thesis and structureeactivity relationships of the lb-methyl-
carbapenems having
a
50-(1-methoxyimino-2-substituted
sulfonamide ethyl)pyrrolidin-30-ylthio group as a C-2 side
chain and our approach for improvement of antibacterial ac-
tivity of the carbapenems was discussed.
* Corresponding author. Tel.: þ82 2 958 5160.
E-mail address: choh@kist.re.kr (C.-H. Oh).
0223-5234/$ - see front matter Ó 2006 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.10.006

H. Jeon et al. / European Journal of Medicinal Chemistry 42 (2007) 358e364
359
OH
O
OH
O
OH
O
CH3
CH3
CH3
O
O
S
S
S
N
N
H
NHSO2NH2
COONa
N
N
N
NH
NH
NH
COOH
COOH
COOH
1, Meropenem
2, Ertapenem
3, S-4661
2. Results and discussion
Finally, the reaction of 6 [5] with thiols (Iaei) in the pres-
ence of diisopropylethylamine provided the corresponding
2-substituted carbapenems (IIaei). Deprotection of these com-
pounds by treatment of tetrakis(triphenylphosphine)palla-
dium(0) and tributyltin hydride gave the crude products,
which were purified by HP-20 column to give the pure carba-
penems (IIIaei) (Scheme 3).
2.1. Chemistry
Our general synthetic route leading to new carbapenems in-
volved the preparation of appropriately protected thiols con-
taining pyrrolidine ring as a side chain and subsequent
coupling reaction with the carbapenem diphenylphosphate,
followed by deprotection of the resulting protected carbape-
nems in a usual manner.
2.2. Biological activity
Acid 1 was treated with N,N0-carbonyldiimidazole and potas-
sium salts of nitromethane, generated in situ from nitromethane
and potassium t-butoxide in THF, to provide 2, which was also
successfully converted into 3 by treatment with methoxylamine.
The key intermediate 4 was obtained by the reaction of 3 with
indium wire in THF and subsequent treatment with methanesul-
fonyl chloride, ethanesulfonyl chloride, methylsulfamoyl, eth-
ylsulfamoyl, dimethylsulfamoyl chloride, propylsulfamoyl
and acetyl chloride afforded the corresponding N-acylated
products, 5aeh. Deprotection of the trityl group to mercaptans
(Iaeh) was achieved by treatment of 5aeh with trifluoroacetic
acid in the presence of triethylsilane (Scheme 1).
2.2.1. Measurement of in vitro antibacterial 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 in-
oculated with an inoculating device onto agar containing serial
two-fold dilutions of the test compounds. Organisms were incu-
bated at 37 ꢀC for 18e20 h. The MICs of a compound were de-
fined as the lowest concentration that visibly inhibited growth.
2.2.2. Antibacterial activity studies
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 ac-
tivities against Gram-positive to meropenem, and against Gram-
negative bacteria except Pseudomonas aeruginosa to imipenem.
Preparation of aminocarbamoyl compound (5i) was accom-
plished by treatment of compound 4 with trimethylsilyliso-
thiocyanate reagent. Deprotection of the trityl group to
mercaptan (Ii) was achieved by treatment of 5i with trifluoro-
acetic acid in the presence of triethylsilane (Scheme 2).
OCH3
N
O
COOH
NO2
TrS
TrS
i
NO2
TrS
ii
N
N
N
AOC
AOC
AOC
2
3
1
iii
N
OCH3
OCH3
OCH3
N
N
iv
v
NHR
NH2.HCl
NHR
TrS
TrS
HS
N
N
N
AOC
AOC
AOC
Ia-h
5a-h
4
R:a=SO2CH3, b=SO2C2H5 c=SO2NHCH3,
d=SO2NHC2H5 e=SO2N(CH3)2, f=SO2NHC3H7
g=COCH3, h=H
(i) 1. N,N-Carbonyldiimidazole 2. Potassium tert-butoxide, nitromethane, THF (ii) Methoxylamine
hydrochloride, pyidine (iii) indiumwire, HCl, H2O, THF (iv) a=Mesyl chloride b=Ethanesulfonyl chloride
c=Methylsulfamoyl chloride d=ethylsulfamoyl chloride e=Dimethylsulfamoyl chloride f=propylsulfamoyl
chloride g=Acetyl chloride h=Allylchloroformate (v) Trifluoroacetic acid, triethylsilane, CH2Cl2
Scheme 1.

360
H. Jeon et al. / European Journal of Medicinal Chemistry 42 (2007) 358e364
OCH3
OCH3
OCH3
N
N
N
ii
i
NHCONH2
HS
NHCONH2
NH2.HCl
TrS
TrS
N
N
N
AOC
AOC
5i
AOC
4
li
Trimetylsilylisocyanate, CH2Cl2
Trifluoroacetic acid, triethylsilane,CH2Cl2
(i)
(ii)
Scheme 2.
As to the substituents on the pyrrolidine chain, the com-
3.1. (2S,4S )-2-[(1-Oxo-2-nitro)ethyl]-4-tritylthio-1-
pounds IIIcef having alkylaminosulfonamide moieties were
generally more potent than the alkylsulfonamide compounds
IIIaeb. In alkylaminosulfonamide compounds IIIcef, it
also shows that the larger the size of the alkyl substituents,
the lower the activity against Gram-positive and Gram-nega-
tive bacteria. As expected, methylaminosulfonamide com-
pound IIIc with small alkyl group exhibited the most potent
and well balanced activity. Also we observed that acetyl amide
substituted compound IIIg is more potent than aminocarba-
moyl IIIi against all bacteria.
The stability to DHP-I of most compounds was tested and
all the tested compounds were more stable than meropenem.
In particular, the compounds IIIa and IIIc exhibited the
most stability (Table 2).
Comparative in vitro activities of IIIc, meropenem, and
imipenem against 40 bacterial strains were summarized in
Table 3. The selected carbapenem IIIc possessed excellent
in vitro activity against 40 target pathogens except P. aerugi-
nosa, and superior or similar antibacterial activities against
Gram-positive to meropenem, and against Gram-negative bac-
teria to imipenem. Against Klebsiella pneumonise, Escherichia
coil and Enterobacter cloacae IIIc was 2e4 times more active
than the compared meropenem and imipenem.
(allyloxycarbonyl)pyrrolidine (2)
A mixture of acid 1 (4.0 g, 8.5 mmol) and N,N0-carbonyl-
diimidazole (1.6 g, 10.2 mmol) suspended in dry THF
(100 mL) was stirred under nitrogen until the solution was
clear (ca. 1 h). To an ice-cold solution of potassium t-butoxide
(1.1 g, 10.2 mmol) in dry THF (20 mL) was slowly added
nitromethane (2.3 g, 42.5 mmol) at 0 ꢀC, and the mixture stirred
for 30 min at room temperature. The prepared above solution of
the imidazolide of 1 was transferred rapidly under a nitrogen
stream directly to the nitronate salt suspension which was stirred
vigorously at 0e5 ꢀC for 30 min. After stirring for 17 h at room
temperature, the mixturewas neutralized with 1 N HCl, and then
was diluted with H2O (50 mL) and ethyl acetate (100 mL). The
organic layer was dried over anhydrous Na2SO4, concentrated,
and the resulting residue was purified by silica gel column chro-
1
matography (EtOAc:hexane ¼ 1:4) to give 2 (2.8 g, 55%). H
NMR (CDCl3) d 1.98e2.16 (m, 2H), 2.97 (q, 1H, J ¼ 4.3 Hz),
3.14e3.20 (m, 2H), 4.23 (bs, 1H), 4.59 (bs, 2H), 5.26e5.32
(m, 4H), 5.84e5.89 (m, 1H), 7.23e7.36 (m, 9H), 7.50 (d, 6H,
J ¼ 5.4 Hz).
3.2. (2S,4S )-2-[(1-Methoxyimino-2-nitro)ethyl]-4-
tritylthio-1-(allyloxycarbonyl)pyrrolidine (3)
3. Experimental
To a solution of 2 (1.0 g, 2.0 mmol) in dry pyridine (20 mL)
was added dropwise methoxylamine hydrochloride (0.41 mL,
2.4 mmol, 35%) and was stirred for 10 h at 50 ꢀC. The mixture
was evaporated under reduced pressure. The residue was dis-
solved with ethyl acetate and washed with 1 N HCl, 10%
NaHCO3 and brine. The organic layer was concentrated in va-
cuo to give a residue, which was purified by silica gel column
chromatography (EtOAc:hexane ¼ 1:1) to give 3 (0.75 g,
Melting point (mp): Thomas Hoover apparatus, uncor-
rected. UV spectra: Hewlett Packard 8451A UVevis spectro-
photometer. IR spectra: PerkineElmer 16F-PC FT-IR. NMR
spectra: Varian Gemini 300 spectrometer, tetramethylsilane
(TMS) as an internal standard. The mass spectrometry system
was based on a HP5989A MS Engine (Palo Alto, CA, USA)
mass spectrometer with a HP Model 59987A.
OCH3
OH
OCH3
OH
N
CH
OH
H H
N
H H
CH3
3O
OP(OPh)2
H H
CH3
NHR
i
NHR
ii
S
N
N
S
N
NH
N
O
AOC
O
COOAllyl
O
COOAllyl
COOH
6
II a-i
III a-i
R:a=SO2CH3, b=SO2C2H5 c=SO2NHCH3, d=SO2NHC2H5
e=SO2N(CH3)2, f=SO2NHC3H7, g=COCH3, h=H, i=CONH2
n-Bu3SnH, cat. (PPh3)4Pd(0), CH2Cl2
(ii)
N,N-Diisopropylethyl amine, Ia-h
(i)
Scheme 3.

H. Jeon et al. / European Journal of Medicinal Chemistry 42 (2007) 358e364
361
Table 1
In vitro antibacterial activity (MIC, mg/mL) of carbapenem derivatives IIIaei
Strains
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
0.049
IIIg
IIIh
IIIi
IPMa
MPMb
Streptococcus pyogenes 308A
Streptococcus pyogenes 77A
Staphylococcus aureus SG511
Staphylococcus aureus 285
Escherichia coli DC2
0.098
0.195
<0.01
<0.01
0.049
0.098
0.013
0.025
1.56
<0.01
<0.01
0.049
0.098
0.013
0.049
3.12
0.025
0.013
0.195
0.195
0.098
0.098
6.25
<0.01
<0.01
0.049
0.098
0.025
0.025
1.56
<0.01
<0.01
0.098
0.195
0.049
0.195
3.12
<0.01
0.013
0.098
0.195
0.049
0.049
1.56
<0.01
<0.01
0.013
0.013
0.391
0.195
0.781
0.781
0.098
0.098
0.013
<0.01
0.098
0.098
0.025
0.025
0.195
0.025
0.049
0.025
0.098
0.195
0.391
0.195
0.195
0.098
0.195
0.781
0.391
0.195
0.025
0.195
0.195
0.098
0.195
Escherichia coli TEM
Pseudomonas aeruginosa 9027
Salmonella typhimurium
12.5
12.5
12.5
0.781
0.781
0.391
1.56
0.781
0.781
0.025
0.025
0.013
0.025
0.049
0.025
0.195
0.391
0.195
0.098
0.195
0.195
0.049
0.049
0.013
0.098
0.195
0.098
0.098
0.195
0.049
Klebsiella aerogenes 1522E
Enterobactor cloacae 1321E
a
Imipenem.
Meropenem.
b
71%) as a pale yellow oil. 1H NMR (CDCl3) d 1.19e1.96 (m,
2H), 2.06 (bs, 1H), 2.48e2.54 (m, 1H), 2.82 (bs, 1H), 2.94 (bs,
1H), 3.94 (d, 3H, J ¼ 4.6 Hz), 4.60 (d, 2H, J ¼ 9.4 Hz), 5.07e
5.13 (m, 2H), 5.23e5.28 (m, 2H), 5.84e5.89 (m, 1H), 7.23e
7.35 (m, 9H), 7.51 (d, 6H, J ¼ 4.4 Hz).
3H, J ¼ 6.0 Hz), 4.10e4.17 (m, 2H), 4.43e4.59 (m, 3H),
5.21e5.27 (m, 2H), 5.81e5.90 (m, 1H), 7.24e7.34 (m, 9H),
7.44e7.47 (m, 6H).
1
Compound 5d: Yield 61%. H NMR (CDCl3) d 1.20e1.22
(t, 3H, J ¼ 6.3 Hz), 1.87e1.93 (m, 1H), 2.13e2.28 (m, 1H),
3.09 (q, 2H, J ¼ 6.3 Hz), 3.23e3.29 (m, 2H), 3.70e3.88 (m,
5H), 4.44e4.52 (m, 4H), 5.20 (d, 2H, J ¼ 11.4 Hz), 5.78e
5.91 (m, 1H), 7.25e7.37 (m, 9H), 7.46 (d, 6H, J ¼ 7.5 Hz).
3.3. (2S,4S )-2-[(1-Methoxyimino-2-
methanesulfonylamino)ethyl]-4-tritylthio-1-
(allyloxycarbonyl)pyrrolidine (5a)
1
Compound 5e: Yield 46%. H NMR (CDCl3) d 1.85e1.89
(m, 1H), 2.11e2.27 (bs, 1H), 2.77 (s, 3H), 2.89 (s, 3H), 3.48e
3.66 (m, 2H), 3.72e3.80 (bs, 2H), 3.82e3.86 (d, 3H,
J ¼ 6.0 Hz), 4.31e4.50 (m, 3H), 5.23 (d, 2H, J ¼ 9.0 Hz),
5.85e5.90 (m, 1H), 7.24e7.33 (m, 9H), 7.46 (d, 6H,
J ¼ 7.2 Hz).
To a solution of 3 (1.3 g, 2.4 mmol) and indium wire (2.0 g)
in THF (20 mL) were added H2O (2.0 mL) and concentrated
HCl (1.5 mL), and stirred at room temperature for 4 h. Evap-
oration of the solvent in vacuo gave a crude residue 4. To
above residue and triethylamine (1.0 mL, 7.1 mmol) in dry
CH2Cl2 (50 mL) was added slowly mesyl chloride (0.4 g,
4.7 mmol) at 0 ꢀC and was stirred for 1 h at same temperature.
The mixture was diluted with H2O (100 mL), CH2Cl2
(100 mL) and washed with brine. The organic layer was dried
over anhydrous Na2SO4, concentrated, and the resulting resi-
due was purified by silica gel column chromatography to
1
Compound 5d: Yield 43%. H NMR (CDCl3) d 1.20e1.22
(t, 3H, J ¼ 6.0 Hz), 1.67e1.75 (m, 2H), 1.89e1.95 (m, 1H),
2.19e2.38 (bs, 1H), 3.02 (q, 2H, J ¼ 6.1 Hz), 3.25e3.33 (m,
2H), 3.71e3.92 (m, 5H), 4.41e4.51 (m, 4H), 5.20 (d, 2H,
J ¼ 9.7 Hz), 5.78e5.91 (m, 1H), 7.25e7.37 (m, 9H), 7.46
(d, 6H, J ¼ 7.5 Hz).
1
Compound 5g: Yield 55%. H NMR (CDCl3) d 1.86e1.96
1
(m, 2H), 2.05 (s, 3H), 2.11e2.17 (m, 1H), 2.73e2.82 (m, 1H),
2.91e3.02 (m, 2H), 3.83 (d, 3H, J ¼ 3.9 Hz), 4.39e4.53 (m,
4H), 5.21e5.28 (m, 2H), 5.82e5.91 (m, 1H), 7.20e7.32 (m,
9H), 7.42 (d, 6H, J ¼ 7.5 Hz).
give 5a (0.9 g, 60%) as a pale yellow oil. H NMR (CDCl3)
d 2.01e2.09 (bs, 1H), 2.22e2.28 (m, 1H), 2.75e2.86 (m,
1H), 2.92 (s, 3H), 3.01e3.48 (m, 2H), 3.85 (d, 3H,
J ¼ 5.4 Hz), 4.41e4.62 (m, 3H), 5.25 (d, 2H, J ¼ 18.3 Hz),
5.82e5.93 (m, 1H), 7.21e7.33 (m, 9H), 7.46 (d, 6H,
J ¼ 7.5 Hz).
1
Compound 5h: Yield 57%. H NMR (CDCl3) d 1.87e2.05
(m, 2H), 2.73 (bs, 1H), 2.83e2.89 (bs, 2H), 2.94e2.97 (m,
1H), 3.45e3.49 (m, 2H), 3.88 (d, 3H, J ¼ 3.3 Hz), 4.40e
4.59 (m, 5H), 5.16e5.28 (m, 4H), 5.79e5.82 (m, 2H),
7.22e7.33 (m, 9H), 7.47 (d, 6H, J ¼ 7.6 Hz).
The synthesis of compounds 5beh was carried out by the
same procedure as described for the preparation of 5a.
1
Compound 5b: Yield 68%. H NMR (CDCl3) d 1.24e1.36
(t, 3H, J ¼ 4.2 Hz), 1.92e2.20 (m, 2H), 2.77e2.82 (m, 1H),
2.92e3.10 (m, 3H), 3.63e3.78 (m, 3H), 3.85 (d, 3H,
J ¼ 5.1 Hz), 4.43e4.55 (m, 3H), 5.21e5.28 (m, 2H), 5.79e
5.90 (m, 1H), 7.21e7.33 (m, 9H), 7.46 (d, 6H, J ¼ 3.6 Hz).
3.4. (2S,4S )-2-[(1-Methoxyimino-2-
aminocarbamoyl)ethyl]-4-tritylthio-1-
(allyloxycarbonyl)pyrrolidine (5i)
1
Compound 5c: Yield 55%. H NMR (CDCl3) d 1.86e1.97
(m, 2H), 2.84 (d, 3H, J ¼ 5.4 Hz), 3.57e3.72 (m, 3H), 3.85 (d,
To the above residue (4, 2.0 g, 3.6 mmol) and triethylamine
(0.8 mL, 5.4 mmol) in dry CH2Cl2 (20 mL) was added slowly
trimethylsilyl isocyanate (0.7 mL, 5.4 mmol) at 0 ꢀC and was
stirred for 7 h at same temperature. The mixture was diluted
with H2O (30 mL), CH2Cl2 (40 mL) and washed with brine.
After drying (Na2SO4), the filtrate was concentrated under
Table 2
DHP-I stability of IIIa, IIIc, IIId and IIIi
IIIa
IIIIc
IIId
IIIi
Meropenem
1.00
Imipenem
0.14
DHP-I
1.40
1.32
1.18
1.09

362
H. Jeon et al. / European Journal of Medicinal Chemistry 42 (2007) 358e364
Table 3
Comparative in vitro antibacterial activity of IIIc, meropenem and imipenem against 40 strains (MIC, mg/mL)
Organism
IIIc
IPM
MPM
Organism
IIIc
IPMa
MPMb
Staphylococcus aureus giorgio
Staphylococcus aureus 209P
Staphylococcus aureus 503
Micrococcus luteus ATCC 9341
Streptococcus facium 77A
Streptococcus agalctiae B
Streptococcus durans D
0.03
0.01
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
0.03
0.05
0.01
0.03
0.03
Salmonella paratyphi A
Salmonella typhimurium
Salmonella oranienberg
Salmonella typhi
0.10
0.20
0.20
0.03
0.10
0.10
0.03
0.01
0.05
0.20
0.20
0.40
0.20
0.20
0.40
0.40
0.40
0.05
0.01
0.01
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
0.03
0.05
0.05
0.01
0.10
0.03
0.05
0.03
0.01
0.05
0.05
0.20
0.10
0.10
0.10
0.10
0.05
0.05
0.05
0.03
0.03
0.03
0.01
<0.01
0.03
0.10
0.03
0.05
1.56
1.56
0.80
0.40
0.40
0.03
0.03
0.03
0.05
0.03
0.05
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
0.20
0.20
0.10
0.05
0.20
0.10
Salmonella orion
Salmonella give
Klebsiella pneumonise 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 subtilts ATCC 6633
Bacillus megatherium
Pseudomonas aeruginosa 9027
Pseudomonas aeruginosa 77/2
Pseudomonas aeruginosa 110/2
Pseudomonas aeruginosa 880/2
Pseudomonas cepacia
Escherichia coil 086
Escherichia coil 0114
Escherichia coil 0126
Proteus rettgeri 936
Proteus rettgeri 937
Escherichia coil V6311/65
Escherichia coil TEM
Escherichia coil 1507
Pasteurella multocida
Corynebacterium diphtheriae
Corynebacterium pyogenes
a
Imipenem.
Meropenem.
b
reduced pressure, and the resulting residue was purified by sil-
ica gel column chromatography to give 5i (0.6 g, 31%) as
3.90 (bs, 6H), 4.25 (d, 1H, J ¼ 6.3 Hz), 4.59 (bs, 1H), 4.70
(dd, 1H, J ¼ 4.5 and 12.6 Hz), 4.83 (dd, 1H, J ¼ 4.5 and
12.6 Hz), 5.26e5.34 (m, 4H), 5.43 and 5.49 (2s, 1H), 5.94e
6.02 (m, 2H).
1
a pale yellow oil. H NMR (CDCl3) d 1.89e2.06 (m, 2H),
2.74e2.99 (m, 1H), 3.05e3.26 (bs, 1H), 3.45e3.49 (bs, 2H),
3.82 (d, 3H, J ¼ 2.7 Hz), 4.39e4.57 (m, 4H), 5.20e5.30 (m,
2H), 5.84e5.85 (m, 1H), 7.15e7.33 (m, 9H), 7.45 (d, 6H,
J ¼ 7.2 Hz).
The synthesis of compounds IIbeh was carried out by the
same procedure as described for the preparation of IIa.
Compound IIb: Yield 44%. 1H NMR (CDCl3) d 1.34e1.39
(m, 6H), 1.46 (d, 3H, J ¼ 6.3 Hz), 3.02e3.09 (m, 3H), 3.26 (d,
1H, J ¼ 5.4 Hz), 3.34e3.41 (m, 1H), 3.41e3.68 (m, 3H),
3.89e3.96 (bs, 5H), 4.25 (d, 2H, J ¼ 6.9 Hz), 4.58 (bs, 3H),
4.70 (dd, 1H, J ¼ 5.1 and 13.5 Hz), 4.83 (dd, 1H, J ¼ 5.1
and 13.5 Hz), 5.25e5.33 (m, 4H), 5.42 and 5.48 (2s, 1H),
5.91e6.00 (m, 2H).
3.5. Allyl (1R,5S,6S )-6-[(1R)-hydroxyethyl]-2-[[5-(1-
methoxyimino-2-methanesulfonylamino) ethyl]-1-
(allyloxycarbonyl)pyrrolidin-3-ylthio]-1-
methylcarbapen-2-em-3-carboxylate (IIa)
1
To a solution of 5a (0.4 g, 0.7 mmol) in CH2Cl2 (2.0 mL)
was added dropwise triethylsilane (0.3 mL, 1.5 mmol) at
5 ꢀC, and then TFA (1.5 mL). After stirring for 30 min at
room temperature, 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
concentrated in vacuo to give a residue Ia, which was used
without further purification. A solution of allyl (1R,5S,6S )-
2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methyl
carbapen-2-em-3-carb-oxylate (6, 0.6 g, 1.2 mmol) in CH3CN
(10 mL) was cooled to 0 ꢀC under N2. To this solution was
added diisopropylethylamine (0.1 g, 1.0 mmol) and a solution
of the mercapto compound Ia in CH3CN (5.0 mL). After stir-
ring 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 sil-
ica gel chromatography (EtOAc:n-hexane ¼ 3:1) to give IIa
Compound IIc: Yield 32%. H NMR (CDCl3) d 1.26 (d,
3H, J ¼ 6.4 Hz), 1.34 (d, 3H, J ¼ 6.6 Hz), 2.18 (bs, 2H),
2.72e2.81 (bs, 4H), 3.26e3.34 (m, 1H), 3.73e3.85 (m, 2H),
3.90 (bs, 4H), 4.27 (d, 2H, J ¼ 6.3 Hz), 4.60 (d, 3H,
J ¼ 7.5 Hz), 4.70 (dd, 1H, J ¼ 5.7 and 12.0 Hz), 4.83 (dd,
1H, J ¼ 5.4 and 11.4 Hz), 5.11 (m, 1H), 5.29 (d, 4H,
J ¼ 11.1 Hz), 5.44 and 5.50 (2s, 1H), 5.9.2e6.01 (m, 2H).
Compound IId: Yield 52%. 1H NMR (CDCl3) d 1.18e1.39
(m, 6H), 1.48 (d, 3H, J ¼ 6.4 Hz), 2.05 (bs, 2H), 3.08e3.12
(m, 2H), 3.35e3.42 (m, 1H), 3.65e3.79 (m, 3H), 3.83e3.89
(m, 5H), 4.24e4.33 (bs, 2H), 4.49e4.54 (bs, 3H), 4.72 (dd,
1H, J ¼ 5.4 and 11.0 Hz), 5.24 (dd, 1H, J ¼ 5.4 and
11.0 Hz), 5.25e5.33 (m, 4H), 5.48 and 5.42 (2s, 1H), 5.92e
6.01 (m, 2H).
1
Compound IIe: Yield 54%. H NMR (CDCl3) d 1.28 (m,
3H), 1.40 (d, 3H, J ¼ 6.2 Hz), 1.88 (m, 2H), 2.06e2.15 (bs,
2H), 2.82e2.98 (bs, 5H), 3.01 (bs, 1H), 3.60e3.77 (m, 3H),
3.89 (s, 3H), 4.11e4.25 (m, 3H), 4.50 (d, 3H, J ¼ 3.0 Hz),
4.60 (bs, 1H), 4.70 (dd, 1H, J ¼ 6 and 15.0 Hz), 4.82 (dd,
1H, J ¼ 5.4 and 16.0 Hz), 5.28 (d, 3H, J ¼ 13.2 Hz), 5.43
and 5.49 (2s, 1H), 5.92e5.97 (m, 2H).
1
(0.3 g, 36%) as a yellow amorphous solid. H NMR (CDCl3)
d 1.24e1.29 (m, 3H), 1.40 (d, 3H, J ¼ 14.6 Hz), 2.05 (bs,
2H), 2.16 (d, 2H, J ¼ 11.0 Hz), 2.27e2.35 (m, 1H), 2.57 (bs,
1H), 2.98 (s, 3H), 3.37e3.42 (m, 1H), 3.35e3.69 (m, 1H),

H. Jeon et al. / European Journal of Medicinal Chemistry 42 (2007) 358e364
363
CompoundIIf:Yield52%. 1HNMR(CDCl3)d1.18e1.39(m,
6H), 1.48 (d, 3H, J ¼ 6.4 Hz), 1.77e1.89 (bs, 2H), 2.05e2.11
(bs, 2H), 3.08e3.12 (m, 2H), 3.34e3.46 (m, 1H), 3.68e3.76
(m, 3H), 3.83e3.89 (m, 5H), 4.24e4.33 (bs, 2H), 4.59e4.654
(bs, 3H), 4.70 (dd, 1H, J ¼ 5.4 and 11.0 Hz), 5.22 (dd, 1H,
J ¼ 5.4 and 11.0 Hz), 5.25e5.33 (m, 4H), 5.48 and 5.42 (2s,
1H), 5.92e6.01 (m, 2H).
2H), 4.13e4.17 (m, 2H). IR (KBr): 3460, 1730, 1710, 1650,
1310 cmꢂ1
eHRMS (FAB) Calcd. for C19H30N4O7S2
490.1556, found 490.15555.
.
1
Compound IIIc: Yield 23%. UV lmax: 298 nm. H NMR
(D2O) d 1.11 (d, 3H, J ¼ 7.2 Hz), 1.18 (d, 3H, J ¼ 6.3 Hz),
2.06e2.17 (m, 1H), 2.55 (bs, 3H), 2.70e2.801 (m, 1H),
3.23e3.37 (m, 3H), 3.57e3.64 (m, 1H), 3.77 (bs, 2H), 3.88
(bs, 4H), 4.12e4.16 (m, 2H), 4.41 (t, 1H, J ¼ 9.3 Hz). IR
(KBr): 3460, 1740, 1710, 1630 1320 cmꢂ1. eHRMS (FAB)
Calcd. for C18H29N5O7S2 491.1508, found 491.1500.
Compound IIg: Yield 49%. 1H NMR (CDCl3) d 1.25e1.29
(m, 3H), 1.38 (d, 3H, J ¼ 6.0 Hz), 1.81e1.90 (m, 1H), 2.04 (s,
3H), 2.50e2.74 (m, 1H), 3.25e3.37 (m, 3H), 3.61 (bs, 1H),
3.89 (s, 3H), 4.03e4.15 (m, 3H), 4.23e4.24 (m, 2H), 4.59
(d, 3H, J ¼ 5.4 Hz), 4.71 (dd, 1H, J ¼ 6.9 and 12.9 Hz), 4.85
(dd, 1H, J ¼ 7.8 and 17.4 Hz), 5.26e5.34 (m, 4H), 5.43 and
4.48 (2s, 1H), 5.92e6.01 (m, 2H).
1
Compound IIId: Yield 25%. UV lmax: 298 nm. H NMR
(D2O) d 1.07 (d, 3H, J ¼ 7.1 Hz), 1.13 (d, 3H, J ¼ 8.1 Hz),
1.20 (t, 3H, J ¼ 6.0 Hz), 1.85e2.04 (m, 1H), 2.08e2.21 (m,
1H), 2.96e3.00 (m, 2H), 3.18e3.25 (m, 1H), 3.30e3.39 (m,
4H), 3.71e3.81 (m, 2H), 3.85e3.90 (m, 4H), 4.13e4.18 (m,
2H). IR (KBr): 3490, 1735, 1710, 1640, 1290 cmꢂ1. eHRMS
(FAB) Calcd. for C19H31N5O7S2 505.1665, found 505.1663.
1
Compound IIh: Yield 31%. H NMR (CDCl3) d 1.26 (d,
3H, J ¼ 6.6 Hz), 1.34 (d, 3H, J ¼ 6.3 Hz), 2.04e2.12 (bs,
2H), 3.24 (bs, 1H, J ¼ 5.7 Hz), 3.31e3.45 (m, 2H), 3.87e
3.97 (bs, 5H), 4.24 (d, 2H, J ¼ 7.5 Hz), 4.50e4.56 (m, 6H),
4.68 (dd, 1H, J ¼ 5.7 and 13.2 Hz), 4.81 (dd, 1H, J ¼ 5.4
and 13.5 Hz), 5.20e5.32 (m, 6H), 5.41 and 5.47 (2s, 1H),
5.92e6.03 (m, 3H).
1
Compound IIIe: Yield 21%. UV lmax: 298 nm. H NMR
(D2O) d 1.10e1.21 (m, 6H), 1.86e1.94 (m, 1H), 2.71 (s,
6H), 2.92e3.05 (m, 2H), 3.24e3.38 (m, 3H), 3.52e3.73 (m,
4H), 3.83 (s, 3H), 4.04e4.16 (m, 2H). IR (KBr): 3540,
1720, 1670, 1620, 1310 cmꢂ1. eHRMS (FAB) Calcd. for
C18H28N4O7S2 476.1399, found 476.1396.
1
Compound IIi: Yield 42%. H NMR (CDCl3) d 1.26 (m,
3H), 1.38 (d, 3H, J ¼ 6.0 Hz), 2.20e2.15 (bs, 2H), 2.98e
3.09 (m, 2H), 3.26e3.41 (m, 1H), 3.87e3.95 (bs, 6H),
4.10e4.16 (m, 1H), 4.25e4.30 (d, 1H, J ¼ 6.0 Hz), 4.38e
4.55 (bs, 4H), 4.69 (dd, 1H, J ¼ 4.2 and 9.0 Hz), 4.80 (dd,
1H, J ¼ 4.2 and 9.0 Hz), 5.29e5.35 (m, 3H), 5.47 and 5.52
(2s, 1H), 5.92e5.97 (m, 2H).
1
Compound IIIf: Yield 22%. UV lmax: 298 nm. H NMR
(D2O) d 1.07 (d, 3H, J ¼ 7.1 Hz), 1.13 (d, 3H, J ¼ 8.1 Hz),
1.20 (t, 3H, J ¼ 6.0 Hz), 1.65e1.77 (m, 2H), 1.89e2.01 (m,
1H), 2.08e2.25 (m, 1H), 2.90e3.03 (m, 2H), 3.22e3.29 (m,
1H), 3.30e3.39 (m, 4H), 3.71e3.85 (m, 2H), 3.85e3.90 (m,
4H), 4.13e4.20 (m, 2H). IR (KBr): 3490, 1735, 1710, 1650,
3.6. (1R,5S,6S )-6-[(1R)-Hydroxyethyl]-2-[[5-(1-
methoxyimino-2-methanesulfonylamino)ethyl]
pyrrolidin-3-ylthio]-1-methylcarbapen-2-em-3-
carboxylic acid (IIIa)
1300 cmꢂ1
519.1821, found 519.1820.
. eHRMS (FAB) Calcd. for C20H33N5O7S2
1
Compound IIIg: Yield 24%. UV lmax: 298 nm. H NMR
(D2O) d 1.11 (d, 3H, J ¼ 7.2 Hz), 1.20 (d, 3H, J ¼ 6.3 Hz),
1.93e2.02 (bs, 4H), 2.66e2.77 (m, 1H), 3.23e3.31 (m, 2H),
3.35e3.41 (m, 1H), 3.56e3.67 (m, 2H), 3.86 (s, 3H), 3.94
(bs, 2H), 4.10e4.15 (m, 2H), 4.33e4.37 (m, 1H). IR (KBr):
3510, 1730, 1710, 1670, 1620 cmꢂ1. HRMS (FAB) Calcd.
for C19H28N4O6S 440.1730, found 440.1730.
To a stirred solution of IIa (0.1 g, 0.2 mol) and Pd(PPh3)4
(30 mg) in CH2Cl2 (10 mL) was added dropwise n-tributyltin
hydride (0.2 mL, 0.5 mmol) at 0 ꢀC and was stirred for 1 h at
same temperature. The resulting solution was diluted with wa-
ter (10 mL) and the organic layers were washed with water
(2 ꢁ 10 mL). The combined aqueous layers were washed
with ethyl ether (2 ꢁ 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 nmwerecollectedandlyophilizedagaintogivethetitlecom-
pound IIIa as an amorphous solid. Yield 24%. UV lmax: 298 nm.
1H NMR (D2O) d 1.12 (d, 3H, J ¼ 7.2 Hz), 1.19 (d, 3H,
J ¼ 6.6 Hz), 1.84e1.95 (m, 1H), 3.03e3.15 (m, 4H), 3.30e
3.46 (m, 3H), 3.56e3.72 (m, 2H), 3.85e3.97 (m, 5H), 4.13e
1
Compound IIIh: Yield 19%. UV lmax: 298 nm. H NMR
(D2O) d 1.11 (d, 3H, J ¼ 7.2 Hz), 1.20 (d, 3H, J ¼ 6.3 Hz),
1.90e1.98 (bs, 1H), 2.06e2.18 (m, 1H), 2.66e2.77 (m, 1H),
3.24e3.57 (m, 4H), 3.70e3.94 (m, 5H), 4.08e4.15 (m, 2H),
4.36e4.50 (m, 1H). IR (KBr): 3440, 1710, 1690,
1630 cmꢂ1
398.1624, found 398.1620.
. eHRMS (FAB) Calcd. for C17H26N4O5S
1
Compound IIIi: Yield 22%. UV lmax: 298 nm. H NMR
(D2O) d 1.12 (d, 3H, J ¼ 7.1 Hz), 1.19 (d, 3H, J ¼ 6.3 Hz),
2.12 (bs, 1H), 2.69e2.76 (m, 1H), 3.25e3.37 (m, 2H), 3.50e
3.59 (m, 2H), 3.63e3.74 (m, 2H), 3.79e3.86 (m, 1H), 3.91 (s,
3H), 4.06e4.17 (m, 2H), 4.36e4.50 (m, 1H). IR (KBr) 3490,
1710, 1690, 1670, 1620 cmꢂ1. eHRMS (FAB) Calcd. for
C18H27N5O6S 441.1682, found 441.1680.
4.20 (m, 3H). IR (KBr): 3480, 1720, 1670, 1630, 1320 cmꢂ1
.
eHRMS (FAB) Calcd. for C18H28N4O7S2 476.1399, found
476.1396.
The synthesis of compounds IIIbei was carried out by the
same procedure as described for the preparation of IIIa.
1
Compound IIIb: Yield 27%. UV lmax: 298 nm. H NMR
Acknowledgement
(D2O) d 1.12 (d, 3H, J ¼ 7.1 Hz), 1.19e1.29 (m, 6H), 3.10e
3.18 (m, 3H), 3.25e3.37 (m, 3H), 3.55e3.57 (m, 1H), 3.63
(bs, 2H), 3.65e3.71 (m, 1H), 3.84 (s, 3H), 3.87e3.89 (m,
We would like to thank Hawon Pharmaceuticals Co. which
was supported with fund.

364
H. Jeon et al. / European Journal of Medicinal Chemistry 42 (2007) 358e364
[7] M. Sato, M. Takemura, S. Atarashi, K. Higashi, T. Nagahara,
References
M. Furukawa, T. Ikeuchi, Y. Osada, J. Antibiot. 40 (1987) 1292e1302.
[8] Y. Iso, T. Irie, Y. Nishino, K. Motokawa, Y. Nishitani, J. Antibiot. 49
(1996) 199e209.
[1] W.J. Leanza, K.J. Wildonger, T.W. Miller, B.G. Christensen, J. Med.
Chem. 22 (1979) 1435e1436.
[9] K. Inoue, Y. Hamana, T. Inoue, M. Fukasawa, M. Kato, Abstracts of Pa-
pers of 34th Intersci. Conf. On Antimicrob. Agents Chemother., No. 1,
Orlando, 1994
[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] N. Sato, F. Ohba, Drugs Future 21 (1996) 361e365.
[11] C.-H. Oh, J.-H. Cho, J. Antibiot. 47 (1994) 126e128.
[12] 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.
[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.
[13] C.-H. Oh, S.-C. Lee, J.-H. Cho, Eur. J. Med. Chem. 38 (2003) 751e758.
[14] C.-H. Oh, S.-C. Lee, J.-H. Cho, Eur. J. Med. Chem. 41 (2006) 50e55.
[5] D.H. Shih, F.L. Baker, B.G. Christensen, Heterocycles 21 (1984) 29e40.
[6] D.H. Shih, B.G. Christensen, Tetrahedron Lett. 26 (1985) 587e590.