Synthesis and Antibacterial Activity of 1β-Methyl-2-(5-substituted Imidazolino Pyrrolidin-3-ylthio)carbapenem Derivatives

Article abstract of DOI:10.1002/ardp.200300756

The synthesis of a new series of 1β-methylcarbapenems containing a substituted imidazolino pyrrolidine moiety is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of the sub

Full text of DOI:10.1002/ardp.200300756

504 Oh et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 504–509
Chang-Hyun Oh,
Chang-Sik Lee,
Jong-Sun Lee,
Jung-Hyuck Cho
Synthesis and Antibacterial Activity of
1␤-Methyl-2-(5-substituted Imidazolino
Pyrrolidin-3-ylthio)carbapenem Derivatives
Medicinal Chemistry
Research Center,
Korea Institute of Science and
Technology,
The synthesis of a new series of 1β-methylcarbapenems containing a substituted
imidazolino pyrrolidine moiety is described. Their in vitro antibacterial activities
against both Gram-positive and Gram-negative bacteria were tested and the effect
of the substituent on the imidazoline ring was investigated. Compound 13 g, which
has a N-sulfonylmethyl substituted imidazoline moiety showed the most potent anti-
bacterial activity.
Seoul 130-650, Korea
Keywords: 1β-Methylcarbapenem; Antibacterial activity; Substituent effect
Received: December 17, 2002; Accepted: February 20, 2003 [FP756]
DOI 10.1002/ardp.200300756
In this paper, we described the synthesis and structure-
activity relationships of lβ-methylcarbapenems having a
Introduction
A number of carbapenem antibiotics, such as imipenem,
panipenem and meropenem, are currently in clinical use
due to their broad antibacterial spectra and potent bac-
tericidal effects [1]. However, they are limited in their use
due to a number of problems. In particular, their activity
against resistant Gram-positive bacteria such as methi-
cillin-resistant Staphylococcus aureus (MRSA) and the
Gram-negative pathogen Pseudomonas aeruginosa, is
relatively weak. During the past decade, extensive syn-
thetic efforts have been made to confer anti-MRSA activ-
ity on β-lactams such as cephalosporin [2, 3] or carba-
penem [4, 5]. These include introducing hydrophobic
functional groups into the C-3 or C-7 side chain of the
cephalosporin nucleus or the C-2 side chain of the
carbapenem nucleus. As a result of these efforts, some
cephalosporin and carbapenem derivatives, with potent
in vitro anti-MRSA activity, have been identified.
5'-substituted imidazolino pyrrolidin-3'-ylthio group as
the C-2 side chain.Our approach to improve the antibac-
terial activity of carbapenems is discussed.
Chemistry
Our synthetic route for generation of new carbapenems
involved the preparation of appropriately protected thiols
containing a pyrrolidine ring as a side chain and then a
coupling reaction with the carbapenem diphenylphos-
phates, followed by deprotection of the resulting protect-
ed carbapenems.
2-(N- or 3-Substituted imidazolino)pyrrolidine deriva-
tives (10 a–k) were prepared by the sequence illustrated
in Scheme 1. N-Protected proline methyl ester was con-
verted to the O-mesylated compound 2 by treatment first
with mesyl chloride and then sodium triphenylmethyl-
thioate generated in situ from triphenylmethylmercaptan
and sodium.
Studies on carbapenem antibiotics, especially the SAR
related to meropenem [6, 7] and panipenem [8], have
shown that the pyrrolidine ring is important for potent ac-
tivity and high PBP affinity. Thus, we postulated that a
combination of these two factors in a single side chain
might lead to agents with a broader spectrum of activity
and anti-MRSA activity.
Hydride in DMF was used for inversion of the C-4 config-
uration of 3.The formation of imidazoline ring 4 was ac-
complished by reaction of 3 with ethylene diamine in the
presence of trimethylaluminum. N-Alkylation of 4, with
alkyl and aryl halide in the presence of base produced
5 b–e. Treatment of 4 with acetyl chloride and mesyl
chloride resulted in the corresponding N-acetylated
products 5 f and 5 g.
Previously, we reported that carbapenem compounds
containing a pyrrolidine-3-ylthio group in the C-2 position
of the carbapenem skeleton have broad and potent anti-
bacterial activity. A large number of derivatives of these
compounds have been synthesized and investigated
[9–13].
Compounds 6 and 8 were prepared by the same proce-
dure described for preparation of 4 using 1,2-diamino-
propane and 1,2-diamino-2-methyl propane instead of
ethylenediamine. The same procedure used to prepare
5 a and 5 g was also employed to generate 7 h–i and
9 j–k.
Correspondence: Chang-Hyun Oh, Medicinal Chemistry
Research Center, Korea Institute of Science and Technology,
Seoul 130-650, Korea. Fax: +82
choh@kist.re.kr
2 958-5189, email:
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2003, 336, 504–509
In vitro antibacterial activity of new carbapenems 505
Scheme 1.
Scheme 2.
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

506 Oh et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 504–509
Deprotection of the trityl group to mercaptan (10 a–k)
was achieved by treatment of trifluoroacetic acid in the
presence of triethylsilane (Scheme 1).
nosa, the larger the size of the substituent, the lower the
activity detected. As expected, the N-sulfonylmethyl sub-
stituted compound 13 g exhibited the most potent and well
balanced activity. Introduction of a methyl group on the
imidazoline ring (13 h–k) significantly lowered the anti-
bacterial activity compared to compounds 13 a and 13 g.
Reaction of 11 [11] with thiols (10 a–k) in the presence of
diisopropylethylamine resulted in the corresponding 2-
substituted carbapenems (12 a–k). Deprotection of
these compounds by catalytic hydrogenation gave crude
products, which were purified by HP-20 column chroma-
tography to give the pure carbapenems (13 a–k)
(Scheme 2).
The stability of most compounds to DHP-I was also test-
ed. All compounds were either similar or more stable
than Meropenem.
Experimental
Antibacterial activity studies
Melting point (mp): Thomas Hoover apparatus, uncorrected.
-UV spectra: Hewlett Packard 8451A UV-VIS spectrophotome-
ter. – IR spectra: Perkin Elmer 16F-PC FT-IR. – NMR spec-
tra: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.
The in vitro antibacterial activities of the new carbapen-
ems (13 a–k) against Gram-positive and negative bacte-
ria are shown inTable 1.For comparison, the MIC values
of Imipenem and Meropenem are also listed. Com-
pounds 13 b, 13 e and 13 g showed similar or superior
antibacterial activity against Gram-positive bacteria
compared to Meropenem, and exhibited improved anti-
bacterial activity against Gram-negative bacteria com-
pared to Imipenem (except P. aeruginosa).
Measurement of In Vitro antibacterial activity
The MICs were determined by the agar dilution method using
test agar. An overnight culture of bacteria in tryptosoy broth
was diluted to about 106 cells/mL with the same broth and inoc-
ulated with an inoculating device onto agar containing serial
twofold dilutions of the test compounds. Organisms were incu-
bated at 37 °C for 18–20 h. The MICs of a compound was de-
fined as the lowest concentration that visibly inhibited growth.
The effects of substituents on the imidazoline ring were
investigated. We found that, with the exception of the
activity of compound 13 g against Pseudomonas aerugi-
Table 1. In vitro antibacterial activity(MIC, µg/mL) and DHP-I stability of the carbapenem derivatives.
STRAINS
13 a 13 b 13 c 13 d 13 e 13 f 13 g 13 h 13 i
13 j 13 k
Imi-
Mero-
pene m pene m
1
2
Streptococcus pyogenes
308A
Streptococcus pyogenes
77A
Staphylococcus aureus
SG511
Staphylococcus aureus
285
Eschericihia coli
DC2
Eschericihia coli
TEM
Psudemonas aeruginosa
9027
Salmonella typhimurium
0.01 0.01 0.05 0.01 0.01 0.01 <0.01 0.02 0.02 0.02 0.01 <0.01
0.02 0.01 0.03 0.01 0.01 0.01 0.01 0.02 0.02 0.05 0.02 <0.01
0.20 0.05 0.20 0.10 0.03 0.20 0.10 0.20 0.20 0.40 0.20 0.01
0.40 0.10 0.40 0.10 0.05 0.20 0.20 0.20 0.10 0.40 0.20 0.01
0.05 0.05 0.10 0.10 0.05 0.10 0.01 0.20 0.10 0.20 0.20 0.40
0.20 0.05 0.20 0.05 0.10 0.10 0.01 0.10 0.20 0.20 0.10 0.20
0.01
<0.01
0.10
0.10
0.03
0.03
0.20
0.03
0.05
0.03
1.00
3
4
5
6
7
3.10 3.10 12.5 50.0 1.56 12.5 0.40 100 50.0
100 100
0.80
8
0.20 0.10 0.40 0.80 0.20 0.20 0.05 0.40 0.40 0.80 0.40 0.80
0.20 0.05 0.40 0.40 0.10 0.40 0.03 0.40 0.40 0.80 0.20 0.10
0.80 0.05 0.20 0.80 0.05 0.20 0.01 0.20 0.20 0.40 0.20 0.10
1.23 1.05 0.85 1.11 1.33 1.16 1.01 1.23 1.12 1.34 1.20 0.19
9
Klebsiella aerogenes
1522E
Enterobactor cloacae
1321E
10
DHP-I
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2003, 336, 504–509
In vitro antibacterial activity of new carbapenems 507
(2S,4S)-2-(N-Allyloxycarbonylimidazolin-2-yl)-4-tritylthio-1-
(allyloxycarbonyl)pyrrolidine (5 a)
Determination of susceptibility to renal dehydropeptidase-I
(DHP-I)
Allyl chloroformate (0.27 g, 2.2 mmol) at 0 °C was slowly added
to a solution of 4 (1.00 g, 2.0 mmol) and triethylamine (0.30 mL,
2.2 mmol) in dry CH2Cl2 (20 mL) and the mixture was stirred for
1 h at 0 °C. It was diluted with H2O (100 mL) and CH2Cl2
(100 mL) and then washed with brine. The organic layer was
dried over anhydrous Na2SO4, concentrated, and the resulting
residue was purified by silica gel column chromatography to
give 5 a (0.85 g, 72.5 %) as a pale yellow oil. 1H-NMR (CDCl3) δ
1.95 (m, 1 H), 2.20 (m, 1 H), 2.98 (m, 1 H), 3.16–3.22 (bs, 2 H),
3.58–3.67 (bs, 4 H), 4.40 (m, 1 H), 4.55 (m, 4 H), 5.23 (m, 4 H),
5.92 (m, 2 H), 7.23 (m, 9 H), 7.48 (m, 6 H).
The relative hydrolysis rate of carbapenems, by porcine renal
DHP-I, was determined by taking the initial hydrolysis rate of
imipenem as 1.0.Partially purified porcine DHP-I (final concen-
tration, 0.3 U/mL) was incubated with 50 µM carbapenem at
35 °C in 50 mM MOPS (Morpholinepropanesulfonic acid) buff-
er (pH 7.0).The initial hydrolysis rate was monitored by spectro-
photometry. One unit of activity was defined as the amount of
enzyme needed to hydrolyze 1 µM of glycyldehydrophenyl-
alanine per min when the substrate (50 µM), was incubated at
35 °C in 50 µM MOPS buffer, pH 7.0.
5 f, 5 g were prepared as described for 5 a using the corre-
sponding acetyl chloride or mesyl chloride.
(2S,4R)-4-Mesyloxy-1-(allyloxycarbonyl)pyrrolidine-2-carb-
oxylic acid methyl ester (2)
5 f:Yield 74.2 %. 1H-NMR (CDCl3) δ 1.97 (m, 1 H), 2.03 (s, 3 H),
2.31 (m, 1 H), 2.95 (m, 1 H), 3.18 (bs, 2 H), 3.65–3.95 (bs, 4 H),
4.40 (m, 1 H), 4.55 (bs, 2 H), 5.25 (m, 2 H), 5.91 (m, 1 H), 7.21
(m, 9 H), 7.48 (m, 6 H).
A solution of 1 (92.5 g, 0.41 mol) and triethylamine (65.0 mL,
0.49 mol) in dry CH2Cl2 (600 mL) was cooled to 0 °C under ni-
trogen and treated with methanesulfonyl chloride (56.0 g,
0.49 mol). The mixture was stirred at 0 °C for 1 h, diluted with
CH2Cl2 (500 mL), and washed with 10 % NaHCO3 and brine.
The organic layer was dried over anhydrous Na2SO4. Evapora-
tion of the solvent in vacuo gave a crude residue, which was pu-
rified by silica gel column chromatography to give 2 (117.4 g,
93.2 %) as a pale yellow oil. 1H-NMR (CDCl3) δ 2.27 (m, 1 H),
2.75 (m, 1 H), 3.06 (s, 3 H), 3.77 and 3.80 (2s, 3 H), 3.82–3.97
(m, 2 H), 4.42 (m, 1 H), 4.57 (d, 2 H, J = 5.8 Hz), 5.25 (m, 3 H),
5.92 (m, 1 H).
1
5 g: Yield 76.6 %. H-NMR (CDCl3) δ 1.89 (m, 1 H), 2.33 (m,
1 H), 2.93 (m, 1 H), 3.01 (s, 3 H), 3.12 (bs, 2 H), 3.63–3.95 (bs,
4 H), 4.40 (m, 1 H), 4.55 (m, 4 H), 5.23 (m, 4 H), 5.92 (m, 2 H),
7.23 (m, 9 H), 7.48 (m, 6 H).
(2S,4S)-2-(N-Methylimidazolin-2-yl)-4-tritylthio-1-(allyloxycar-
bonyl)pyrrolidine (5 b)
A solution of 4 (0.90 g, 1.98 mmol) in dry CH3CN (10 mL) under
N2 gas was added slowly to a solution of potassium carbonate
(0.27 g, 1.98 mmol) in dry CH3CN (20 mL). After 1 h, methyl
iodide (2.81 g, 19.8 mmol) was added dropwise to the reaction
mixture and it was stirred for 24 h at room temperature.The re-
sulting mixture was diluted with ethyl acetate (50 mL). The or-
ganic layer was washed with brine and dried over anhydrous
Na2SO4. Removal of the solvent gave a crude residue, which
was chromatographed on silica gel using ethyl acetate as the
eluent to give 5 b (0.57 g, 62.0 %) as a pale yellow oil. 1H-NMR
(CDCl3) δ 1.86 (m, 1 H), 2.25 (m, 1 H), 2.92 (m, 1 H), 3.05 (s,
3 H), 3.19–3.23 (bs, 2 H), 3.68–3.90 (bs, 4 H), 4.33 (m, 1 H),
4.55 (bs, 2 H), 5.23 (m, 2 H), 5.93 (m, 1 H), 7.23 (m, 9 H), 7.48
(m, 6 H).
(2S,4S)-4-Tritylthio-1-(allyloxycarbonyl)pyrrolidine-2-carboxylic
acid methyl ester (3)
Sodium hydride (11.6 g, 0.29 mol, 60 % oil suspension) at 0 °C
was added dropwise to a stirred solution of triphenylmethyl-
mercaptan (80.0 g, 0.29 mol) in dry DMF (600 mL) and stirred
for 1 h at room temperature. A solution of 2 (76.7 g, 0.25 mol) in
dry DMF (150 mL) at 0 °C was added and the mixture was
stirred for 3 h at room temperature. The reaction mixture 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 to give 3 (100.6 g, 82.5 %) as a pale yellow oil.
1H-NMR (CDCl3) δ 2.01 (m, 1 H), 2.55 (m, 1 H), 3.16 (bs, 1 H),
3.54 (bs, 1 H), 3.77 and 3.80 (2s, 3 H), 3.97 (m, 1 H), 4.42 (m,
1 H), 4.55 (d, 2 H, J = 5.5 Hz), 5.26 (m, 2 H), 5.98 (m, 1 H), 7.23
(m, 9 H), 7.48 (m, 6 H).
5 c, 5 d and 5 e were prepared as described for 5 b using the
corresponding aryl bromide or alkyl bromide.
5 c:Yield 68.3 %. 1H-NMR (CDCl3) δ 1.02, 1.06 (2s, 6 H), 1.97
(m, 1 H), 2.31 (m, 1 H), 2.95–3.04 (m, 2 H), 3.18–3.33 (bs, 2 H),
3.35–3.55 (bs, 3 H), 4.33 (m, 1 H), 4.40 (m, 1 H), 4.55 (bs, 2 H),
5.25 (m, 2 H), 5.91 (m, 1 H), 7.21 (m, 9 H), 7.48 (m, 6 H).
1
5 d: Yield 70.1 %. H-NMR (CDCl3) δ 1.99 (m, 1 H), 2.30 (m,
(2S,4S)-2-(Imidazolin-2-yl)-4-tritylthio-1-(allyloxycarbonyl)-
pyrrolidine (4)
1 H), 2.97–3.03 (m, 2 H), 3.19–3.33 (bs, 2 H), 3.35–3.59 (bs,
3 H), 4.40–4.49 (m, 3 H), 4.51 (bs, 2 H), 5.25 (m, 2 H), 5.90 (m,
1 H), 7.21–7.27 (m, 14 H), 7.48 (m, 6 H).
2 M trimethylaluminum (55.0 mL, 0.11 mol) at 0 °C was added
dropwise to a stirred solution of ethylenediamine (7.39 g,
0.11 mol) in dry toluene (200 mL) and the mixture was stirred
for 1 h at room temperature. A solution of 3 (26.8 g, 0.055 mol)
in dry toluene (150 mL) at 0 °C was added and the mixture was
stirred for 15 h at 50 °C. MeOH (100 mL) and water (200 mL)
were added and the reaction was stirred for an additional
30 min. The resulting precipitates were filtered off and the fil-
trate washed with water, dried over MgSO4, and evaporated.
The residue was purified by silica gel column chromatography
to give 4 (18.7 g, 68.5 %) as a pale yellow oil.1H-NMR (CDCl3) δ
1.99 (m, 1 H), 2.11 (m, 1 H), 3.16–3.22 (bs, 2 H), 3.48–3.67 (bs,
5 H), 4.42 (m, 1 H), 4.55 (m, 2 H), 5.23 (m, 2 H), 5.92 (m, 1 H),
7.23 (m, 9 H), 7.48 (m, 6 H).
1
5 e: Yield 65.8 %. H-NMR (CDCl3) δ 2.04 (m, 1 H), 2.13 (m,
1 H), 2.72–2.78 (m, 2 H), 3.21–3.29 (m, 4 H), 3.23–3.40 (bs,
2 H), 3.53 (m, 1 H), 3.65–3.75 (m, 2 H), 4.40 (m, 1 H), 4.55 (bs,
4 H), 5.25 (m, 4 H), 5.88 (m, 2 H), 7.21 (m, 9 H), 7.46 (m, 6 H).
(2S,4S)-2-(4-Methylimidazolin-2-yl)-4-tritylthio-1-(allyloxycar-
bonyl)pyrrolidine (6)
Synthesis of compound 6 was carried as described for prepara-
tion of 4 using 1,2-diaminopropane instead of ethylenediamine.
Yield 41.3 %. 1H-NMR (CDCl3) δ 1.06 (d, 3H, J=5.9 Hz), 2.01
(m, 1 H), 2.11 (m, 1 H), 2.95–3.12 (bs, 2 H), 3.22–3.28 (bs, 1 H),
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

508 Oh et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 504–509
Compounds 10 b–k were synthesized using the same proce-
dure as described for the preparation of 10 a.
3.48–3.67 (bs, 2 H), 4.31 (m, 1 H), 4.42 (m, 1 H), 4.55 (bs, 2 H),
5.25 (m, 2 H), 5.88 (m, 1 H), 7.23 (m, 9 H), 7.48 (m, 6 H).
(2S,4S)-2-(N-Allyloxycarbonyl-4-methylimidazolin-2-yl)-4-tri-
tylthio(allyloxycarbonyl) pyrrolidine (7 h)
Allyl
(1R,5S,6S)-6-[(1R)-hydroxyethyl]-3-[5-(N-Allyloxycar-
bonylimidazolin-2-yl)]-1-(allyloxyca rbonyl)pyrrolidin-3-ylthio]-
1-methylcarbapen-2-em-3-carboxylate (12 a)
Compound 7 h was prepared as described for preparation of
5 a.
A solution of allyl (1R,5S,6S)-3-(diphenylphosphoryloxy)-6-
[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (11,
0.50 g, 1.0 mmol) in CH3CN (10 mL) was cooled to 0 °C under
N2. Diisopropylethylamine (0.13 g, 1.0 mmol) and a solution of
the mercapto compound 10 a (0.34 g, 1.0 mmol) in CH3CN
(5 mL) was added. After stirring for 5 h, the mixture was diluted
with ethyl acetate, washed with 10 % NaHCO3 and brine, and
dried over anhydrous MgSO4. Evaporation in vacuo gave a
foam, which was purified by silica gel chromatography to give
12 a (0.45 g, 71.6 %) as a yellow foam solid. 1H-NMR (CDCl3) δ
1.16 (d, 3 H, J = 6.5 Hz), 1.28 (d, 3 H, J = 5.7 Hz), 2.15–2.26 (m,
2 H), 2.86 (m, 1 H), 3.21–3.33 (m, 4 H), 3.53–3.60 (m, 2 H), 3.70
(bs, 1 H), 3.95 (m, 1 H), 4.10 (m, 2 H), 4.43 (bs, 1 H), 4.51–4.72
(bs, 6 H), 5.21–5.39 (m, 6 H), 5.81–5.91 (m, 3 H). – IR (KBr):
3410 (OH), 3230 (NH), 1720, 1660 (C=O) cm–1.
Yield 72.7 %. 1H-NMR (CDCl3) δ 1.06 (d, 3 H, J = 5.9 Hz), 2.01
(m, 1 H), 2.11 (m, 1 H), 2.95–3.12 (bs, 2 H), 3.22–3.28 (bs, 1 H),
3.48–3.67 (bs, 2 H), 4.31 (m, 1 H), 4.42 (m, 1 H), 4.55–4.59 (bs,
4 H), 5.24–5.31 (m, 4 H), 5.85–5.90 (m, 2 H), 7.24 (m, 9 H), 7.49
(m, 6 H).
(2S,4S)-2-(N-Mesyl-4-methylimidazolin-2-yl)-4-tritylthio-1-(allyl-
oxycarbonyl)pyrrolidine (7 i)
Compound 7 i was prepared using the same procedure as
described for generation of 5 g.
Yield 41.3 %. 1H-NMR (CDCl3) δ 1.09 (d, 3 H, J = 5.9 Hz), 2.06
(m, 1 H), 2.19 (m, 1 H), 2.99–3.13 (bs, 2 H), 3.04 (s, 3 H), 3.22–
3.26 (bs, 1 H), 3.49–3.64 (bs, 2 H), 4.33 (m, 1 H), 4.42 (m, 1 H),
4.55 (bs, 2 H), 5.25 (m, 2 H), 5.88 (m, 1 H), 7.23 (m, 9 H), 7.48
(m, 6 H).
Compounds 12 b–k were prepared by the same procedure as
described for the generation of 12 a.
(2S,4S)-2-(4,4-Dimethylimidazolin-2-yl)-4-tritylthio-1-(allyloxy-
carbonyl)pyrrolidine (8)
(1R,5S,6S)-6-[(1R)-hydroxyethyl]-3-[5-(imidazolin-2-yl)]pyrroli-
din-3-ylthio]-1-methylcarbapen -2-em-3-carboxylic acid (13 a)
Compound 8 was prepared using the same procedure as de-
scribed for the preparation of 4 using 1,2-diamino-2-methyl
propane instead of ethylenediamine.
Compound 12 a (0.31 g, 0.50 mmol) and 0.1 g of Pd(OH)2
(20 %) were dissolved in THF/phosphate buffer (pH = 7) (1:1,
10 mL each). The mixture was hydrogenated at 50 psi for 1 h.
The solution was filtered through celite and washed with water
(2 × 10 mL).The combined filtrate was washed with ethyl ether
(2 × 20 mL) and lyophilized to give a yellow powder which was
purified on a Diaion HP-20 column, using 2 % THF in water as
the eluent. Fractions having a UV absorption at 298 nm were
collected and lyophilized again to give the title compound 13 a
Yield 39.3 %. 1H-NMR (CDCl3) δ 1.18 (s, 6 H), 2.19 (m, 2 H),
3.16–3.55 (bs, 3 H), 3.68–3.97 (bs, 1 H), 4.42 (m, 2 H), 4.55 (m,
2 H), 5.23 (m, 2 H), 5.92 (m, 1 H), 7.23 (m, 9 H), 7.48 (m, 6 H).
(2S,4S)-2-(N-Allyloxycarbonyl-4,4-dimethylimidazolin-2-yl)-4-
tritylthio-1-(allyloxycarbonyl) pyrrolidine (9j)
Compound 9 j was prepared using the same procedure as
described for the preparation of 5 a.
1
(55 mg, 29.1 %) as a white powder. – UV λmax: 298 nm. – H-
NMR (D2O) δ 1.10 (d, 3 H, J = 6.5 Hz), 1.16 (d, 3 H, J = 5.7 Hz),
1.99–2.03 (m, 1 H), 2.86 (m, 1 H), 3.11–3.23 (m, 2 H), 3.31–
3.43 (m, 4 H), 3.63–3.67 (m, 2 H), 3.70 (bs, 1 H), 3.95 (m, 1 H),
4.10 (m, 1 H), 4.51 (bs, 1 H). – IR (KBr): 3470 (OH), 3230 (NH),
1710, 1690 (C=O) cm–1. – FABMS m/z 381 (M + H)+.
Yield 59.3 %. 1H-NMR (CDCl3) δ 1.18 (s, 6 H), 2.11 (m, 1 H),
2.18 (m, 1 H), 3.16–3.55 (bs, 3 H), 3.68–3.97 (bs, 1 H), 4.42 (m,
2 H), 4.55–4.60 (bs, 4 H), 5.23–5.28 (m, 4 H), 5.86–5.90 (m,
2 H), 7.23 (m, 9 H), 7.45 (m, 6 H).
(2S,4S)-2-(N-Mesyl-4,4-dimethylimidazolin-2-yl)-4-tritylthio-1-
(allyloxycarbonyl)pyrrolidine (9 k)
Compounds 13 b–k were generated by a procedure similar to
that described for the synthesis of 13 a
13 b:Yield 18.1 %. – UV λmax: 298 nm. – 1H-NMR (D2O) δ 1.10
Compound 9 k was prepared using the same procedure as
described for the preparation of 5 g.
(d, 3 H, J = 6.5 Hz), 1.14 (d, 3 H, J = 6.0 Hz), 2.02–2.06 (m, 1 H),
2.83 (m, 1 H), 2.88 (s, 3 H), 3.11–3.28 (m, 3 H), 3.31–3.40 (m,
3 H), 3.60–3.69 (m, 2 H), 3.70 (bs, 1 H), 3.99 (m, 1 H), 4.11 (m,
1 H), 4.45 (bs, 1 H). – IR (KBr): 3470 (OH), 3230 (NH), 1705,
1685 (C=O) cm–1. – FABMS m/z 395 (M + H)+.
Yield 60.5 %. 1H-NMR (CDCl3) δ 1.13 (s, 6 H), 2.05 (m, 1 H),
2.21 (m, 1 H), 3.02 (s, 3 H), 3.19–3.51 (bs, 2 H), 3.58–3.69 (bs,
2 H), 4.41 (m, 2 H), 4.56 (bs, 2 H), 5.23 (m, 2 H), 5.86 (m, 1 H),
7.23 (m, 9 H), 7.45 (m, 6 H).
13 c:Yield 21.4 %.– UV λmax:298 nm.– mp 115–123 °C (dec.).–
1H-NMR (D2O) δ 1.02 (d, 6 H, J = 7.1 Hz), 1.12 (d, 3 H, J = 6.6
Hz), 1.22 (d, 3 H, J = 6.3 Hz), 2.23 (m, 1 H), 2.89 (m, 1 H), 3.11–
3.20 (m, 2 H), 3.31–3.49 (m, 4 H), 3.60–3.73 (m, 2 H), 3.75 (bs,
1 H), 3.99 (m, 1 H), 4.11 (bs, 1 H), 4.25 (m, 1 H), 4.55 (m, 1 H).–
IR (KBr): 3480 (OH), 3230 (NH), 1710, 1690 (C=O) cm–1. –
FABMS m/z 423 (M + H)+.
(2S,4S)-2-(N-Allyloxycarbonylimidazolin-2-yl)-4-mercapto-1-
(allyloxycarbonyl)pyrrolidine (10 a)
Triethylsilane (0.13 g, 1.1 mmol) at 5 °C was added dropwise to
a solution of 5 a (0.58 g, 1.0 mmol) in CH2Cl2 (2 mL) and then
TFA (2 mL) was added.After stirring for 30 min at room temper-
ature, 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, which was purified by silica gel column
chromatography to give 10 a (0.20 g, 58.9 %) as a pale yellow
13 d:Yield 19.9 %. – UV λmax: 298 nm. – mp 132–142 °C (dec.).
– 1H-NMR (D2O) δ 1.05 (d, 3 H, J = 6.7 Hz), 1.15 (d, 3 H, J = 6.0
Hz), 2.13 (m, 1 H), 2.89 (m, 1 H), 3.11–3.22 (m, 2 H), 3.31–3.51
(m, 4 H), 3.60–3.73 (m, 2 H), 3.79 (bs, 1 H), 3.99 (m, 1 H), 4.11
(m, 2 H), 4.29 (s, 2 H), 4.44 (bs, 1 H), 7.29 (bs, 5 H). – IR (KBr):
3490 (OH), 3230 (NH), 2990 (Ar), 1710, 1690 (C=O) cm–1. –
FABMS m/z 471 (M + H)+.
1
oil. H-NMR (CDCl3) δ 1.97 (m, 1 H), 2.50 (m, 1 H), 2.93 (m,
1 H), 3.16 (bs, 2 H), 3.68–3.97 (bs, 4 H), 4.40 (m, 1 H), 4.55–
4.60 (m, 4 H), 5.23–5.27 (m, 4 H), 5.87–5.92 (m, 2 H).
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2003, 336, 504–509
In vitro antibacterial activity of new carbapenems 509
3.44 (m, 2 H), 3.61–3.68 (m, 2 H), 3.82 (bs, 1 H), 3.99 (m, 1 H),
4.15 (m, 1 H), 4.49 (bs, 1 H). – IR (KBr): 3510 (OH), 3320 (NH),
1710, 1660 (C=O), 1225 (S=O) cm–1. – FABMS m/z 487 (M +
H)+.
13 e:Yield 17.7 %.– UV λmax:296 nm.– mp 130–135 °C (dec.).–
1H-NMR (D2O) δ 1.07 (d, 3 H, J = 6.5 Hz), 1.18 (d, 3 H, J =
6.1 Hz), 2.13 (m, 1 H), 2.89 (m, 1 H), 3.11–3.22 (m, 2 H), 3.31–
3.53 (m, 6 H), 3.61–3.78 (m, 4 H), 3.83 (bs, 1 H), 3.95 (m, 1 H),
4.14 (m, 1 H), 4.48 (bs, 1 H). – IR (KBr): 3510 (OH), 3300 (NH),
1700, 1660 (C=O) cm–1. – FABMS m/z 425 (M + H)+.
13 f:Yield 21.2 %.– UV λmax:298 nm.– 1H-NMR (D2O) δ 1.09 (d,
3 H, J = 6.5 Hz), 1.16 (d, 3 H, J = 6.0 Hz), 2.02 (s, 3 H), 2.11 (m,
1 H), 2.80 (m, 1 H), 3.11–3.22 (m, 2 H), 3.33–3.50 (m, 4 H),
3.61–3.72 (m, 2 H), 3.89 (bs, 1 H), 3.95 (m, 1 H), 4.19 (m, 1 H),
4.54 (bs, 1 H). – IR (KBr): 3510 (OH), 3270 (NH), 1710, 1680
(C=O) cm–1. – FABMS m/z 423 (M + H)+.
References
[1] S. Coultion, E. Hunt in Progress In Medicinal Chemistry
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1996, 49, 402–404.
13 g:Yield 14.8 %. – UV λmax: 298 nm. – 1H-NMR (D2O) δ 1.08
(d, 3 H, J = 7.3 Hz), 1.22 (d, 3 H, J = 6.8 Hz), 2.03 (m, 1 H), 2.80
(m, 1 H), 3.01 (s, 3 H), 3.10–3.20 (m, 2 H), 3.31–3.53 (m, 4 H),
3.61–3.78 (m, 2 H), 3.89 (bs, 1 H), 3.95 (m, 1 H), 4.11 (m, 1 H),
4.44 (bs, 1 H). – IR (KBr): 3480 (OH), 3260 (NH), 1710,1690
(C=O), 1220 (S=O) cm–1. – FABMS m/z 459 (M + H)+.
[3] O. K. Kim,Y. Udea, M. Mansuri, J.W. Russel, Bioorg. Med.
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Chem. Lett. 1995, 5, 1427–1432.
13 h:Yield 21.1 %. – UV λmax: 298 nm. – 1H-NMR (D2O) δ 0.99
(d, 3 H, J = 7.0 Hz), 1.09 (d, 3 H, J = 7.3 Hz), 1.20 (d, 3 H, J = 6.9
Hz), 2.06 (m, 1 H), 2.69 (m, 1 H), 3.10–3.18 (m, 2 H), 3.33–3.53
(m, 3 H), 3.61–3.70 (m, 2 H), 3.82 (bs, 1 H), 3.99 (m, 1 H), 4.10
(m, 1 H), 4.44 (bs, 1 H).– IR (KBr):3510 (OH), 3320 (NH), 1710,
1670 (C=O) cm–1. – FABMS m/z 395 (M + H)+.
[5] H. Shinagawa, H.Yamaga, H. Houchigai,Y. Sumita, M. Su-
naga, Bioorg. Med. Chem. 1997, 5, 601–621.
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[7] M. Sunagawa, H. Matsumure, T. Inoue, M. Fukasawa, M.
Kato, J. Antibiot. 1990, 43, 519–532.
13 i:Yield 20.4 %.– UV λmax:298 nm.– mp 111–123 °C (dec.).–
1H-NMR (D2O) δ 0.98 (d, 3 H, J = 7.0 Hz), 1.09 (d, 3 H, J = 7.0
Hz), 1.20 (d, 3 H, J = 6.5 Hz), 2.03 (m, 1 H), 2.88 (m, 1 H), 3.02
(s, 3 H), 3.10–3.18 (m, 2 H), 3.33–3.53 (m, 3 H), 3.61–3.72 (m,
2 H), 3.83 (bs, 1 H), 3.99 (m, 1 H), 4.13 (m, 1 H), 4.55 (bs, 1 H).–
IR (KBr): 3500 (OH), 3320 (NH), 1710, 1660 (C=O), 1260
(S=O) cm–1. – FABMS m/z 473 (M + H)+.
[8] T.Miyadera,T.Sugimura,T.Hasimoto,T.Tanaka, K.Iino, S.
Sugawara, J. Antibiot. 1983, 36, 1034–1039.
[9] C.-H. Oh, J.-H. Cho, J. Antibiot. 1994, 47, 126–128.
[10] K.-H. Nam, C.-H. Oh, J.K. Cho, K.-S. Lee, J.-H. Cho, Arch.
Pharm. Pharm. Med. Chem. 1996, 329, 289–291.
13 j:Yield 11.5 %.– UV λmax:298 nm.– 1H-NMR (D2O) δ 0.95 (s,
6 H), 1.09 (d, 3 H, J = 7.3 Hz), 1.16 (d, 3 H, J = 6.9 Hz), 2.06 (m,
1 H), 2.74 (m, 1 H), 3.10–3.18 (m, 2 H), 3.33–3.44 (m, 2 H),
3.61–3.68 (m, 2 H), 3.82 (bs, 1 H), 3.99 (m, 1 H), 4.15 (m, 1 H),
4.49 (bs, 1 H). – IR (KBr): 3470 (OH), 3230 (NH), 1720, 1690
(C=O) cm–1. – FABMS m/z 409 (M + H)+.
[11] C.-H. Oh, Y. H. Ham, K.-S. Lee, J.-H. Cho, Arch. Pharm.
Pharm. Med. Chem. 1997, 330, 268–270.
[12] C.-H.Oh, H.-W.Cho, I.-K.Lee, J.-Y.Gong, J.-H.Choi, J.-H.
Cho, Arch. Pharm. Pharm. Med. Chem. 2002, 335, 152–
158.
13 k:Yield 13.3 %. – UV λmax: 298 nm. – 1H-NMR (D2O) δ 0.95
(s, 6 H), 1.11 (d, 3 H, J = 7.3 Hz), 1.16 (d, 3 H, J = 6.9 Hz), 2.06
(m, 1 H), 2.79 (m, 1 H), 3.03 (s, 3 H), 3.10–3.18 (m, 2 H), 3.33–
[13] C.-H.Oh, H.-G.Dong, H.-W.Cho, S.J.Park, J.H.Hong, J.-
H. Cho, Arch. Pharm. Pharm. Med. Chem. 2002, 335,
200–206.
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim