Synthesis and antibacterial activity of 1β-methyl-2-[5-(1,2- disubstituted ethyl)pyrrolidin-3-ylthio]carbapenem derivatives

Article abstract of DOI:10.1002/ardp.200500139

The synthesis of a new series of 1β-methylcarbapenems having a 5-(1,2-disubstituted ethyl) 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.200500139

Arch. Pharm. Chem. Life Sci. 2006, 339, 67–73
S.-H. Ahn et al.
67
Short Communication
Synthesis and Antibacterial Activity of 1b-Methyl-2-[5-(1,2-
Disubstituted Ethyl)Pyrrolidin-3-ylthio]Carbapenem
Derivatives
Soo-Hyun Ahn1, Heechol Jeon1, Joung-Hoon Choi1, Daejin Baek2, Seon Hee Seo3,
Jung-Hyuck Cho3, Chang-Hyun Oh3
1 Department of Chemistry, Hanyang University, Seoul, Korea
2 Department of Chemistry, Hanseo University, Seosan, Korea
3 Medicinal Chemistry Research Center, Korea Institute of Science and Technology, Seoul, Korea
The synthesis of a new series of 1b-methylcarbapenems having a 5-(1,2-disubstituted ethyl) pyrro-
lidine 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 pyrrolidine ring was
investigated. A particular compound IIIf having a 1-methoxyimino-2-carbamoylethyl substituted
moiety showed the most potent antibacterial activity.
Keywords: 1b-Methylcarbapenem / Antibacterial activity / Substituent effect /
Received: May 25, 2005; accepted: September 19, 2005
DOI 10.1002/ardp.200500139
Introduction
Results and discussion
The carbapenem compounds which have a (3S)-pyrroli- Chemistry
din-3-ylthio group at the C-2 position in the carbapenem Our general synthetic route leading to new carbapenems
skeleton are noted for their broad and potent antibacter- involved the preparation of appropriately protected
ial activity [1] and a large number of derivatives have thiols containing a pyrrolidine ring as a side chain and a
been synthesized and investigated [2–7].
subsequent coupling reaction with the carbapenem
We conceived that introduction of an additional meth- diphenylphosphates, followed by deprotection of the
oxyimine and oxime moiety to the pyrrolidine side chain resulting protected carbapenems in a usual manner. 5-
was responsible for the improvements, because the com- (1,2-disubstituted ethyl)pyrrolidinethiol derivatives (Ia-i)
pounds having methoxyimine and oxime moiety have were prepared by the sequence shown in Schemes 1-3.
shown to enhance drug activity in general.
The b-keto ester 2 was obtained from carboxylic acid 1
In this paper, we describe the synthesis and structure- with ethyl malonate magnesium salt [8] by means of 1,19-
activity relationship of lb-methylcarbapenems having a carbonyldiimidazole. The b-keto ester 2 was converted to
59-(1,2-disubstituted ethyl)pyrrolidin-39-ylthio group as a the hydroxy compound 3 by treatment of sodium borohy-
C-2 side chain and our approach for improvement of anti- dride in THF. Preparation of the oxime 4 and methoxy-
bacterial activity of the carbapenems is discussed.
imino compound 5 was accomplished by treatment of
the b-keto ester 2 with hydroxyl and methoxyl amines
(Scheme 1).
The treatment of the b-keto ester 2 with ammonia in
MeOH gave the amide 6, which was successfully con-
verted into the derivatives 7, 8, and 9 using the same pro-
cedure as described for the preparation of 3, 4, and 5
(Scheme 2).
Correspondence: Chang-Hyun Oh, Medicinal Chemistry Research Cen-
ter, Korea Institute of Science and Technology, 39-1 Hawolgokdong,
Seongbukgu Seoul, 130-650 Korea.
E-mail: choh@kist.re.kr
Fax: +82 2 958-5189
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Arch. Pharm. Chem. Life Sci. 2006, 339, 67–73
(i) ethyl malonate Mg salt, N,N9-carbonyldiimidazole, THF; (ii) NaBH4, THF; (iii) trifluoroacetic acid,
triethylsilane, CH2Cl2; (iv) hydroxylamine, EtOH; (v) methoxylamine hydrochloride, pyridine.
Scheme 1. Preparation of the compounds Ia–Ic.
(i) ammonia gas, MeOH; (ii) NaBH4, THF; (iii) trifluoroacetic acid, triethylsilane, CH2Cl2; (iv) hydroxyl-
amine, EtOH; (v) methoxylamine hydrochloride, pyridine.
Scheme 2. Preparation of compounds Id–If.
The acid 1 was treated with 1,19-carbonyldiimidazole pounds by treatment of tetrakis(triphenylphosphine)pal-
and potassium salts of nitromethane, generated in situ ladium and tributyltin hydride gave the crude products,
from nitromethane and potassium t-butoxide in THF to which were purified on a HP-20 column to give the pure
provide 10, which was also successfully converted into carbapenems IIIa–i (Scheme 4).
the 11, 12, and 13 using the same procedure as described
for the preparation of 3, 4, and 5 (Scheme 3).
Biological assay
Deprotection of the trityl group to mercaptans Ia-i was Measurement of in vitro antibacterial activity: The MICs
achieved by treatment of 3–13 with trifluoroacetic acid were determined by the agar dilution method using test
in the presence of triethylsilane.
agar. An overnight culture of bacteria in tryptosoy broth
Finally, the reaction of 14 [9] with thiols Ia–i in the pre- was diluted to approx. 106 cells/mL with the same broth
sence of diisopropylethylamine provided the 2-substi- and inoculated with an inoculating device onto agar con-
tuted carbapenem IIa–i. Deprotection of these com- taining serial twofold dilutions of the test compounds.
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Arch. Pharm. Chem. Life Sci. 2006, 339, 67–73
Novel Carbapenem Derivatives
69
(i) potassium-tert butoxide, nitromethane, THF; (ii) NaBH4, THF; (iii) trifluoroacetic acid, triethylsilane,
CH2Cl2; (iv) hydroxyl amine, EtOH; (v) methoxylamine hydrochloride, pyridine.
Scheme 3. Preparation of compounds Ig–Ii.
(i) N,N9-Diisopropylethyl amine Ia-I; (ii) tetrakis(triphenylphosphine)palladium, tributyltin hydride, CH2Cl2.
Scheme 4. Preparation of carbapenems IIIa–i.
Organisms were incubated at 37 8C for 18–20 h. The
As to the substituent of the 1,2-disubstituted ethyl side
MICs of a compound was defined as the lowest concentra- chain, the compounds IIId-f having an amide group were
tion that visibly inhibited growth.
generally more potent than the ester and nitro groups.
As expected, the existence of a nitro group (IIIg and IIIi)
significantly lowered the antibacterial activity compared
Antibacterial activity studies
The in vitro antibacterial activities of the new carbape- to compounds with ester and amide groups. Also, intro-
nems IIIa–i prepared above against Gram-positive and - duction of methoxyimine group (IIIc and IIIf) led to sig-
negative bacteria are listed in Table 1. For comparison, nificantly inhanced antibacterial activity against Gram-
the MIC values of imipenem and meropenem are also negative bacteria compared to hydroxy (IIIa, IIId, and
listed. Among these compounds, IIIa and IIIf showed IIIg) and oxime group (IIIb, IIIe, and IIIh). As a result,
superior or similiar antibacterial activity against Gram- compound IIIf having methoxyimine and amide group
positive bacteria to meropenem and exhibited improved exhibited the most potent and well balanced activity.
antibacterial activity against Gram-negative bacteria
than imipenem.
Comparative in vitro activities of IIIf, meropenem, and
imipenem against 40 bacterial strains were summarized
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Table 1. In vitro antibacterial activity (MIC, lg/mL) of the carbapenem derivatives.
STRAINS
IIIa
3.125
IIIb
IIIc
IIId
IIIe
IIIf
3.125
IIIg
IIIh
IIIi
IPMa)
MPMb)
Staphylococcus aureus 1218
Coagulase negative staphylococci
Enterococcus faecalis 2347
Streptococcus pyogenes 9889
Streptococcus agalactiae 32
Haemophilus influenzae 1210
Escherichia coli 04
Klebsiella peneumoniae 523
Citrobacter freundii 323
Enterobactor cloacae 34
25
25
12.500
0.195
12.500
0.007
0.049
12.500
0.195
0.391
0.195
0.195
0.391
12.500
3.125
25
12.500
1.560
12.500
0.007
0.049
12.500
0.098
0.391
0.098
0.195
0.391
12.5
25
3.125
25
25
1.563
0.025
1.563
0.004
0.013
6.250
0.195
0.781
0.391
0.781
0.781
12.500
3.125
6.250
0.098
12.500
0.007
0.049
3.125
0.025
0.025
0.025
0.025
0.049
6.250
3.125
0.098
3.125
0.013
0.013
3.125
0.025
0.098
0.049
0.049
0.098
12.500
6.250
1.563
50
0.391
0.781
25
0.025
0.098
25
0.098
3.120
0.098
0.195
0.195
1.563
25
0.049
0.195
25
0.195
0.781
0.391
0.391
0.781
0.098
12.500
0.013
0.007
6.250
0.007
0.049
0.049
0.049
0.098
12.5
1.560
25
0.013
0.049
3.125
0.013
0.391
0.098
0.049
0.049
12.500
0.195
25
0.391
1.560
0.391
0.195
1.56
25
0.195
12.500
0.781
3.125
0.195
0.391
0.781
25
Serratia marcescens 3349
Acinetobacter baumannii 2289
Psudemonas aeruginosa 5455
25
6.250
25
12.500
25
3.125
25
3.125
3.125
6.250
a)
imipenem.
meropenem.
b)
Table 2. Comparative in vitro antibacterial activity of IIIf, meropenem (MPM), and imipenem (IPM) against 40 strains of bacteria
(MIC, lg/mL).
Organism
IIIf
0.03
IPMa)
MPMb)
Organism
IIIf
IPM)
MPMb)
Staphylococcus aureus giorgio
Staphylococcus aureus 209P
Staphylococcus aureus 503
Micrococcus luteus ATCC 9341
Streptococcus facium 77A
Streptococcus agalactiae B
Streptococcus durans D
Bacillus subtilts ATCC 6633
Bacillus megatherium
Pseudomonas aeruginosa 9027
Pseudomonas aeruginosa 77/2
Pseudomonas aeruginosa 110/2
Pseudomonas aeruginosa 880/2
Pseudomonas cepacia
0.01
0.01
a0.01
0.01
a0.01
0.01
0.10
0.03
0.03
0.80
0.80
0.80
0.80
0.80
0.10
0.10
0.05
0.20
0.10
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
0.01
0.03
0.01
0.05
0.05
Salmonella paratyphi A
Salmonella typhimurium
Salmonella oranienberg
Salmonella typhi
Salmonella orion
Salmonella Give
0.10
0.20
0.20
0.03
0.10
0.10
0.20
0.03
0.01
0.20
0.20
0.40
0.20
0.20
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
0.20
0.20
a0.01
0.03
a0.01
0.03
0.05
0.05
0.01
0.10
0.03
0.05
0.05
0.03
0.05
0.05
0.20
0.10
0.10
0.10
0.05
0.05
0.05
0.03
0.03
0.01
0.01
a0.01
0.03
0.10
0.03
0.05
0.80
0.80
0.80
0.40
0.10
0.05
0.05
0.05
0.10
0.10
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 rettgeri 936
Escherchia coli 086
Escherchia coli 0126
Escherchia coli V6311/65
Escherchia coli TEM
Escherchia coli 1507
Proteus rettgeri 937
Pasteurella multocida
Corynebacterium diphtheriae
Corynebacterium pyogenes
a)
imipenem.
meropenem.
b)
Table 3. Anti-MRS activities.
Table 4. DHP-I stablity of IIIa, IIId, and IIIf (g/mL).
Methicillin resistant strains
IIIa
IIId
IIIf
Vancomycin
IIIa
IIId
IIIf
Meropenem Imipenem
1.00 0.20
Staphylococcus aureus LG001
Staphylococcus aureus LG002
Staphylococcus aureus Y8012954
Staphylococcus aureus QRS179
Staphylococcus aureus QRS241
Staphylococcus aureus Hoechst208E 0.195
Staphylococcus aureus KIST2
Staphylococcus aureus KIST5
1.563
0.391
0.195
0.391
0.391
1.563
0.195
0.195
0.391
0.391
0.195
6.25
0.391
0.098
0.049
0.195
0.195
0.098
1.563
0.195
1.563
0.391
0.391
0.391
0.391
0.391
0.781
0.391
DHP-1
1.22
1.38
1.67
IIIf was 2–3 times more active than the compared mer-
openem and imipenem.
6.25
0.781
0.781
The MRSA activities of the three potent carbapenems
(IIIa, IIId, and IIIf) prepared above are listed in Table 3.
Among these compounds, IIIf showed superior or simi-
liar antibacterial activity to vancomycin. The stability to
DHP-I of potent compounds was tested and all the com-
pounds were more stable than meropenem (Table 4). In
particular, the compounds IIIf was exhibited the most
stability.
in Table 2. The selected carbapenem IIIf possessed excel-
lent in vitro activity against 40 target pathogens except P.
aeruginosa and superior or similar antibacterial activities
against Gram-positive to meropenem, and against Gram-
negative bacteria to imipenem. Against Pseudomonas cepa-
cia, Enterobacter cloacae, and Corynebacterium diphtheriae,
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Arch. Pharm. Chem. Life Sci. 2006, 339, 67–73
Novel Carbapenem Derivatives
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Hz), 1.87–1.89 (m, 2H), 2.44–2.47 (m, 2H), 2.91 (brs, 1H), 3.23
(brs, 1H), 3.40–3.44 (m, 2H), 4.22 (q, 2H, J = 4.6 Hz), 4.54 (brs, 2H),
5.27 (d, 2H, J = 12.4 Hz), 5.83–5.87 (m, 1H), 7.21–7.33 (m, 9H),
7.48 (d, 6H, J = 7.8 Hz).
We would like to thank Hawon Pharmaceuticals Co. which was
supported with fund.
Experimental
(2S,4S)-2-[(1-Methoxyimino-2-ethoxycarbonyl)ethyl]-4-
tritylthio-1-(allyloxycarbonyl) pyrrolidine 5
General
To a solution of 2 (0.7 g, 1.2 mmol) in dry pyridine (20 mL) meth-
oxylamine hydrochloride (0.4 mL, 1.8 mmol, 35%) was added
dropwise and the mixture was stirred for 16 h at 508C. The sol-
vent was evaporated under reduced pressure. The residue was
dissolved with ethyl acetate and washed with 1N HCl, 10%
NaHCO3, and brine. The organic layer was concentrated in vacuo
to give a residue, which was purified by silica gel column chro-
matography (EtOAc:hexane = 1:1) to give 5 (0.50 g, 74.9%) as a
Melting point (Mp.): Thomas Hoover apparatus (Philadelphia,
PA, USA), uncorrected. UV spectra: Hewlett Packard 8451A UV-
VIS spectrophotometer (Hewlett-Packard, Palo Alto, CA, USA). IR
spectra: Perkin Elmer 16F-PC FT-IR (Perkin-Elmer, Norwalk, CT,
USA). NMR spectra: Varian Gemini 300 spectrometer (Varian,
Palo Alto, CA, USA), tetramethylsilane (TMS), as an internal stan-
dard. The mass spectrometry system was based on a HP5989A MS
Engine mass spectrometer with a HP Model 59987A.
1
pale yellow oil. H-NMR (CDCl3) d 1.25 (t, 3H, J = 4.4 Hz), 1.96–
2.01 (m, 2H), 2.55–2.57 (m, 1H), 2.83 (brs, 2H), 3.23 (brs, 2H), 3.72
(s, 1H), 3.81 (s, 3H), 4.25 (q, 2H, J = 4.1 Hz), 4.46–4.51 (m, 2H),
5.21–5.28 (m, 2H), 5.84-5.86 (m, 1H), 7.21–7.38 (m, 9H), 7.49 (d,
6H, J = 7.7 Hz).
Syntheses
(2S,4S)-2-[(1-Oxo-2-ethoxycarbonyl)ethyl]-4-tritylthio-1-
(allyloxycarbonyl)pyrrolidine 2
To a stirred solution of 1 (5.0 g, 10.6 mmol) in dry THF (50 mL) 1,19-
carbonyldiimidazole (2.0 g, 12.7 mmol) was added dropwise at
08C and was stirred for 1 h at room temperature. To the resulting
solution ethylmagnesium malonate(3.2g, 11.0mmol) was added
at room temperature and was stirred for 10 h at the same tem-
perature. The reaction mixture was poured into ice-cold water,
acidified to pH 5–6 with 6N HCl and then extracted with ethyl
acetate. Evaporation of the solvent in vacuo gave a crude residue
which was purified by silica gel column chromatography (EtOA-
c:hexane = 1:3) to give 2 (3.6 g, 62.1%) as a pale yellow oil.1H-NMR
(CDCl3) d 1.23–1.29 (t, 3H, J = 4.5 Hz), 1.72–1.85 (m, 2H), 2.34 (q,
1H, J = 5.3 Hz), 2.99–3.02 (m, 2H), 3.27 (brs, 2H), 3.46-3.50 (m, 1H),
4.21 (q, 2H, J = 4.2 Hz), 4.50 (d, 2H, J = 7.8 Hz), 5.26–5.29 (m, 2H),
5.78-5.80 (m, 1H), 7.23–7.31(m, 9H), 7.47(d, 6H, J = 8.0 Hz).
(2S,4S)-2-[(1-Oxo-2-carbamoyl)ethyl]-4-tritylthio-1-
(allyloxycarbonyl)pyrrolidine 6
To a solution of 2 (2.0 g, 3.7 mmol) in MeOH (30 mL) ammonia gas
was passed through for 1 h at 08C and the mixture was stirred for
20 h at room temperature. The solvent was evaporated under
reduced pressure. The residue was dissolved with ethyl acetate
and washed with 1N HCl, 10% NaHCO3, and brine. The organic
layer was concentrated in vacuo to give a residue which was puri-
fied by silica gel column chromatography (EtOAc:hexane = 3:1 )
1
to give 6 (1.1 g, 58.0%) as a pale yellow oil. H-NMR (DMSOd-6) d
1.89–1.90 (m, 1H), 2.83–2.94 (m, 4H), 3.21–3.24 (m, 1H), 4.36–
4.43 (m, 3H), 5.10–5.21 (m, 2H), 5.71–5.74 (m, 1H), 7.05 (brs, 1H),
7.24–7.30(m, 6H), 7.33–7.47 (m, 9H).
The synthesis of the compounds 7, 8, and 9 were carried out by
the same procedures as described for the preparation of 3, 4, and
5 using compound 2.
(2S,4S)-2-[(1-Hydroxy-2-ethoxycarbonyl)ethyl]-4-
tritylthio-1-(allyloxycarbonyl)pyrrolidine 3
1
7: Yield: 57%. H-NMR (CDCl3) d 1.72–1.77 (m, 2H), 2.12–2.21
To a solution of the mixture 2 (1.5 g, 2.8 mmol) in THF (30 mL)
NaBH4 (0.1 g 2.8 mmol) was added slowly at 08C and was stirred
for 2 h at room temperature. The reaction mixture was poured
into ice-cold water, acidified to pH 4–5 with acetic acid, and
then extracted with ethyl acetate. Evaporation of the solvent in
vacuo gave a crude residue, which was purified by silica gel col-
umn chromatography (EtOAc:hexane = 1:2) to give 3 (0.9 g,
60.1%) as a pale yellow oil. 1H-NMR (CDCl3) d 1.29 (t, 3H, J = 7.1
Hz), 1.96–2.06 (m, 2H), 2.37–2.40 (m, 2H), 2.73 (brs, 2H), 3.01
(brs, 1H), 3.75–3.79 (m, 1H), 4.20 (q, 3H, J = 4.3 Hz), 4.49 (d, 2H, J =
5.5 Hz), 5.22–5.28 (m, 2H), 5.84–5.87 (m, 1H), 7.24–7.33(m, 9H),
7.47 (d, 6H, J = 7.2 Hz).
(m, 2H), 2.70 (brs, 1H), 3.11–3.23 (m, 2H), 3.71 (brs, 1H), 3.88 (brs,
1H), 4.54 (d, 2H, J = 7.1 Hz), 5.21–5.32 (m, 2H), 5.83–5.91 (m, 1H),
7.20–7.45 (m, 9H), 7.48 (d, 6H, J = 5.6 Hz).
1
8: Yield: 57%. H-NMR (CDCl3) d 1.80–1.92 (m, 2H), 2.90–2.96
(m, 1H), 3.24 (s, 2H), 3.38–3.44 (m, 2H), 4.52–4.61 (m, 3H), 5.28
(d, 2H, J = 5.1 Hz), 5.86–5.91 (m, 1H), 7.22–7.35 (m, 9H), 7.48 (d,
6H, J = 7.6 Hz).
1
9: Yield: 61%. H-NMR (DMSO) d 2.02 (brs, 2H), 2.88 (q, 3H, J =
7.2 Hz), 3.01–3.05 (m, 1H), 3.14 (d, 1H, J = 7.1 Hz), 3.74 (t, 3H, J =
7.3 Hz), 4.14–4.17 (m, 1H), 4.37-4.45 (m, 2H), 5.22 (d, 2H, J = 5.2
Hz), 5.7–35.79 (m, 1H), 7.22–7.25 (m, 4H), 7.26–7.43 (m, 11H).
(2S,4S)-2-[(1-Hydroxyimino-2-ethoxycarbonyl)ethyl]-4-
(2S,4S)-2-[(1-Oxo-2-nitro)ethyl]-4-tritylthio-1-
tritylthio-1-(allyloxycarbony) pyrrololidine 4
(allyloxycarbonyl)pyrrolidine 10
To a stirred solution of 2 (2.5 g, 4.6 mmol) in EtOH (30 mL) 50%
aqueous hydroxylamine (0.3 mL, 5.1 mmol) was added dropwise
and was stirred for 7 h at 508C. The reaction mixture was diluted
with ethyl acetate (50 mL) and water (50mL), and the organic
layer was dried over anhydrous Na2SO4. Evaporation of the sol-
vent in vacuo gave a crude residue, which was purified by silica
gel column chromatography (EtOAc:Hexane = 1:1) to give 4 (1.3
g, 54.0%) as a pale yellow oil. 1H-NMR (CDCl3) d 1.33 (t, 3H, J = 4.3
A mixture of acid 1 (4.0 g, 8.5 mmol) and 1,19-carbonyldiimida-
zole (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 08C and the mixture was stirred for 30 min at room tempera-
ture. The prepared above solution of the imidazolide of 1 was
transferred rapidly under a nitrogen stream directly to the nitro-
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Arch. Pharm. Chem. Life Sci. 2006, 339, 67–73
nate salt suspension which was stirred vigorously at 0–58C for
30 min. After stirring for 17 h at room temperature, the mixture
was neutralized with 1N 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 chromatography (EtOAc:hexane =
1:4) to give 10 (2.8 g, 55.0%). 1H-NMR (CDCl3) d 1.98–2.16 (m, 2H),
2.97 (q, 1H, J = 4.3 Hz), 3.14–3.20 (m, 2H), 4.23 (brs, 1H), 4.59 (brs,
2H), 5.26–5.32(m, 4H), 5.84–5.89 (m, 1H), 7.23–7.36 (m, 9H),
7.50 (d, 6H, J = 5.4 Hz).
(m, 2H), 4.49 (brs, 4H), 4.68 (brs, 1H), 4.77 (brs, 1H), 5.40 (brs, 4H),
5.84–5.91 (m, 2H).
IIe: Yield 26%. 1H-NMR (CDCl3) d 1.26–1.38 (m, 6H), 1.60 (s, 3H),
2.29 (brs, 2H), 2.50 (brs, 2H), 3.24–3.27 (m, 1H), 4.12–4.24 (m,
2H), 4.71 (brs, 4H), 4.61–4.69 (m, 1H), 4.72 (brs, 1H), 5.28 (brs,
4H), 5.88–5.96 (m, 2H).
IIf: Yield 33%. 1H-NMR (CDCl3) d 1.19 (d, 3H, J = 6.9 Hz), 1.30 (d,
3H, J = 5.8 Hz), 1.97 (brs, 4.53 (brs, 4H), 4.68 (brs, 1H), 4.77 (brs,
1H), 5.29–5.45 (m, 4H), 5.88–5.97 (m, 2H).
IIg: Yield 33%. 1H-NMR (CDCl3) d 1.26 (d, 3H, J = 7.1 Hz), 1.34 (d,
3H, J = 6.3 Hz), 1.79 (brs, 1H), 3.24–3.33 (m, 3H), 3.68–3.72 (m,
2H), 4.04 (brs, 3H), 4.18–4.20 (m, 2H), 4.60 (d, 4H, J = 4.2 Hz),
4.77–4.78 (m, 1H), 4.82–4.84 (m, 1H), 5.22–5.31 (m, 4H), 5.88–
5.94 (m, 2H).
The synthesis of the compounds 11, 12, and 13 were carried
out by the same procedure as described for the preparation of 3,
4, and 5 using compound 10.
11: Yield: 83%. 1H-NMR (CDCl3) d 1.90–1.97 (m, 2H), 2.73–2.88
(m, 2H), 3.10–3.15 (m, 1H), 3.58 (d, 2H, J = 4.2 Hz), 3.72 (d, 1H, J =
5.2 Hz), 4.49–4.52 (m, 3H), 5.23–5.30 (m, 2H), 5.91–5.98 (m, 1H),
7.23–7.45 (m, 9H), 7.48 (d, 6H, J = 7.5 Hz).
IIh: Yield 17%. 1H-NMR (CDCl3) d 1.19–1.32 (m, 6H), 2.41–2.46
(m, 4H), 3.67 (s, 2H), 3.74–3.78 (m, 2H), 4.07–4.10 (m, 2H), 4.20–
4.22 (m, 2H), 4.62-4.67 (m, 4H), 5.19–5.35 (m, 4H), 5.87–5.93 (m,
2H).
12: Yield: 70%. 1H-NMR (CDCl3) d 2.07 (brs, 2H), 2.80 (q, 1H, J =
6.5 Hz), 2.93 (brs, 2H), 4.01 (brs, 1H), 4.41–4.47 (m, 2H), 4.49–
4.52 (m, 2H), 5.31 (d, 2H, J = 8.4 Hz), 5.79–5.87 (m, 1H), 7.22–7.36
(m, 9H), 7.46 (d, 6H, J = 7.4 Hz).
IIi: Yield 34%. 1H-NMR (CDCl3) d 1.27 (d, 3H, J = 4.8 Hz), 1.33 (d,
3H, J = 6.2 Hz), 2.03 (brs, 1H), 3.12–3.25 (m, 3H), 3.51–3.56 (m,
2H), 3.91 (s, 3H), 4.23 (t, 2H, J = 6.7 Hz), 4.54–4.55 (m, 4H), 4.69–
4.70 (m, 1H), 4.72–4.74 (m, 1H), 5.11 (brs, 2H), 5.44–5.46 (m, 4H),
5.89–5.94 (m, 2H).
13: Yield: 86%. 1H-NMR (CDCl3) d 1.19–1.96 (m, 2H), 2.06 (brs,
1H), 2.48–2.54 (m, 1H), 2.82 (brs, 1H), 2.94 (brs, 1H), 3.94 (d, 3H, J
= 4.6 Hz), 4.60 (d, 2H, J = 9.4 Hz), 5.07–5.13 (m, 2H), 5.23–5.28 (m,
2H), 5.84–5.89 (m, 1H), 7.23–7.35 (m, 9H), 7.51 (d, 6H, J = 4.4 Hz).
(1R, 5S, 6S)-6-[(1R)-Hydroxyethyl]-2-[[5-(1-hydroxy-2-
ethoxycarbonyl)ethyl]pyrrolidin-3-yl thio]-1-
methylcarbapen-2-em-3-carboxylic acid IIIa
Allyl (1R, 5S, 6S)-6-[(1R)-hydroxyethyl]-2-[[5-(1-hydroxy-
2-ethoxycarbonyl)ethyl]-1-(allyl-oxycarbonyl)pyrrolidin-3-
ylthio]-1-methylcarbapen-2-em-3-carboxylate IIa
To a stirred solution of IIa (0.2 g, 0.4 mol) and Pd(PPh3)4 (30 mg) in
CH2Cl2 (10 mL) was added dropwise n-tributyltin hydride (0.2 mL,
0.5 mmol) at 08C and was stirred for 1 h at same temperature. The
resulting solution was diluted with water (10 mL) and the organic
layers was washed with water (2610 mL). The combined aqueous
layers were washed with ethyl ether (2610 mL) and lyophilized
to give a yellow powder which was purified on a Diaion HP-20 col-
umn (Mitsubishi Chemical Co., Tokyo, Japan), eluting with 2%
THF in water. Fractions having UV absorption at 298 nm were col-
lected and lyophilized again to give the title compound IIIa as an
amorphorus solid. Yield 18.3%. UV kmax: 298 nm. Mp.: 161–1638C
(dec.). 1H-NMR (D2O) d 1.12–1.19 (m, 9H), 1.87–1.94 (m, 1H), 2.51–
2.61 (m, 3H), 3.21–3.28 (m, 2H), 3.34–3.36 (m, 1H), 3.60 (brs, 2H),
4.08–4.17 (m, 1H), 4.35–4.37 (m, 4H), 4.65–4.68 (m, 1H). IR (KBr):
3460, 1730, 1710, 1670 cm– 1. HRMS(FAB) Calcd. for C19H28N2O7S
428.1617, Found 428.1613.
To a solution of 3 (0.90 g, 1.7 mmol) in CH2Cl2 (2 mL) triethylsi-
lane (0.3 mL, 1.8 mmol) was added dropwise at 58C, 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 solu-
tion of allyl (1R, 5S, 6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydro-
xyethyl]-1-methylcarbapen-2-em-3-carboxylate (14, 0.60 g, 1.2
mmol) in CH3CN (10 mL) was cooled to 08C under N2. To this solu-
tion diisopropylethyl amine (0.13 g, 1.0 mmol) was added and a
solution of the mercapto compound Ia in CH3CN (5 mL). After
stirring for 6 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 = 3:1) to give IIa
The syntheses of compounds IIIb–i were carried out by the
same procedures as described for the preparation of IIIa.
1
1
(0.38 g, 40.1%) as a yellow amorphous solid. H-NMR (CDCl3) d
IIIb: Yield 21.0%. UV kmax: 298nm. Mp.: 160–1648C (dec.). H-
1.22–1.27 (brs, 6H), 1.34 (d, 3H, J = 3.1 Hz), 2.55 (brs, 3H), 3.05–
3.20 (brs, 2H), 3.40 (brs, 1H), 3.55 (brs, 1H), 3.90 (brs, 1H), 4.05–
4.40 (brs, 6H), 4.45 (brs, 1H), 4.50 (brs, 2H), 4.58 (brs, 1H), 4.65
(brs, 1H), 5.20–5.50 (brs, 4H), 5.89–5.93 (m, 2H).
NMR (D2O) d 1.03 (d, 3H, J = 6.9 Hz), 1.10 (d, 3H, J = 7.4 Hz), 1.16
(brs, 3H), 1.25–1.27 (m, 1H), 2.09 (brs, 2H), 2.20–2.25 (m, 1H),
2.75–2.79 (m, 1H), 2.91–2.93 (m, 1H), 3.31 (brs, 2H), 3.64–3.66
(m, 2H), 3.98–4.03 (m, 2H), 4.13–4.16 (m, 2H). IR (KBr): 3460,
1730, 1710, 1650 cm-1. HRMS(FAB) Calcd. for C19H27N3O7S
441.1570, Found 441.1569.
The synthesis of compounds IIb–i was carried out by the same
procedure as described for the preparation of Ia.
IIb: Yield 37%. 1H-NMR (CDCl3) d 1.26–1.40 (m, 9H), 1.60 (brs,
3H), 2.31–2.40 (m, 2H), 2.98–3.01 (m, 1H), 3.30–3.34 (m, 2H),
3.95–3.97 (m, 2H), 4.14–4.24 (m, 2H), 4.63 (brs, 4H), 4.81 (brs,
1H), 4.90 (brs, 1H), 5.23–5.31 (m, 4H), 5.91–5.97 (m, 2H).
IIIc: Yield 19.2%. UV kmax: 298nm. Mp.: 159–1658C (dec.). H-
1
NMR (D2O) d 1.07–1.22 (m, 9H), 1.90–1.94 (m, 1H), 2.91–2.95 (m,
1H), 3.40–3.44 (m, 3H), 3.65–3.67 (m, 1H), 3.71–3.74 (m, 1H),
3.84 (s, 3H), 3.99–4.03 (m, 1H), 4.17 (q, 4H, J = 7.1 Hz), 4.45–4.46
(m, 2H). -IR (KBr): 3460, 1740, 1710, 1650 cm– 1. HRMS(FAB) Calcd.
for C20H29N3O7S 455.1726, Found 455.1720.
1
IIc: Yield 40%. H-NMR (CDCl3) d 1.24–1.36 (m, 9H), 2.08 (brs,
4H), 3.26–3.37 (m, 3H), 3.85 (s, 3H), 4.11–4.16 (m, 3H), 4.22–4.24
(m, 2H), 4.56 (brs, 4H), 4.71–4.72 (m, 1H), 4.79–4.81 (m, 1H),
5.33–5.47 (m, 4H), 5.87–5.92 (m, 2H).
1
IIId: Yield 17.5%. UV kmax: 298nm. Mp.: 150-1568C (dec.). H-
NMR (D2O) d 1.10 (d, 3H, J = 7.2 Hz), 1.17 (d, 3H, J = 6.3 Hz), 2.06–
2.11 (m, 2H), 2.31–2.43 (m, 2H), 3.29–3.24 (m, 2H), 3.48–3.53
(m, 2H), 4.10–4.12 (m, 2H), 4.15–4.18 (m, 1H), 4.61–4.62 (m, 1H),
IId: Yield 30%. 1H-NMR (CDCl3) d 1.13–1.30 (m, 6H), 1.87 (brs,
4H), 3.16 (brs, 2H), 3.60 (brs, 2H), 3.81–3.89 (m, 1H), 4.09–4.14
i 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2006, 339, 67–73
Novel Carbapenem Derivatives
73
4.70–4.72 (m, 1H). IR (KBr): 3490, 1735, 1710, 1670 cm– 1
HRMS(FAB) Calcd. for C17H25N3O6S 399.1464, Found 399.1465.
.
2H, J = 6.1 Hz), 4.60–4.62 (m, 1H). IR (KBr): 3460, 1710, 1680,
1570 cm– 1. HRMS (FAB) Calcd. for C17H24N4O7S 428.1366, Found
428.1362.
IIIe: Yield 24%. UV kmax: 298nm. Mp.: 152–1568C (dec.). 1H-
NMR (D2O) d 1.06–1.14 (m, 6H), 1.23 (brs, 1H), 2.06 (brs, 2H),
2.91–2.97 (m, 1H), 3.25–3.29 (m, 2H), 3.79–3.84 (m, 2H), 4.01–
4.18 (m, 2H), 4.54 (brs, 1H), 4.68 (brs, 1H). IR (KBr): 3540, 1720,
1700, 1670 cm-1. HRMS(FAB) Calcd. for C17H24N4O6S 412.1417,
Found 412.1416.
References
[1] M. Sato, M. Takemura, S. Atarashi, K. Higashi, T. Naga-
hara, M. Furukawa, T. Ikeuchi, Y. Osada, J. Antibiot. 1987,
40, 1292–1302.
IIIf: Yield 13%. UV kmax: 298nm. Mp.: 158–1638C (dec.). 1H-NMR
(D2O) d 1.10 (d, 3H, J = 7.2 Hz), 1.19 (d, 3H, J = 6.4 Hz), 1.75–1.82
(m, 2H), 2.73–2.77 (m, 1H), 3.28–3.30 (m, 2H), 3.32–3.34 (m, 2H),
3.59–3.63 (m, 1H), 3.79 (s, 3H), 3.95–3.97 (m, 1H), 4.09–4.11 (m,
1H), 4.62 (t, 1H, J = 6.1 Hz), 4.66–4.68 (m, 1H). IR (KBr): 3510,
1730, 1710, 1660 cm– 1. HRMS(FAB) Calcd. for C18H26N4O6S
426.1573, Found 426.1570.
[2] C.-H. Oh, J.-H. Cho, J. Antibiot. 1994, 47, 126–128.
[3] 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 1999, 138, 59–67.
[4] C.-H. Oh, S.-C. Lee, J.-H. Cho, Eur. J. Med. Chem. 2003, 38,
IIIg: Yield 14%. UV kmax: 298nm. Mp.: 162-1708C (dec.). 1H-NMR
(D2O) d 1.14 (d, 3H, J = 4.1 Hz), 1.55 (d, 3H, J = 3.9 Hz), 1.54–1.57
(m, 2H), 2.45–2.49 (m, 2H), 3.33–3.35 (m, 2H), 3.46–3.48 (m, 2H),
3.69–3.74 (m, 3H), 4.10–4.14 (m, 2H). IR (KBr): 3440, 1710, 1670,
1550 cm– 1. HRMS(FAB) Calcd. for C16H23N3O7S 401.1257, Found
401.1255.
751–758.
[5] C.-H. Oh, S.-C. Lee, J.-H. Cho, Eur. J. Med. Chem. 2003, 38,
841–850.
[6] H.-W. Cho, C.-H. Oh, S.-C. Lee, H.-W. Cho, J.-H. Choi, J.-H.
Cho, Arch. Pharm. Pharm. Med. Chem. 2003, 336, 495–503.
IIIh: Yield 10%.UV kmax: 298nm. Mp.: 160–1638C (dec.). 1H-NMR
(D2O) d 0.96–1.26 (m, 6H), 2.32–2.43 (m, 4H), 3.43–3.49 (m, 2H),
3.71–3.79 (m, 4H), 5.01 (d, 2H, J = 4.5 Hz). IR (KBr): 3490, 1710,
1670, 1570 cm– 1. HRMS(FAB) Calcd. for C16H22N4O7 S 414.1209,
Found 414.1203.
[7] J.-S. Lee, H.-W. Cho, J.-H. Cho, C.-H. Oh, Arch. Pharm.
Pharm. Med. Chem. 2004, 337, 391–397.
[8] D. M. Barnes, J. Ji, M. G. Fickes, M. A. Fitzgerald, S. A.
King, H. E. Morton, F. A. Plagge, M. Preskill, S. H. Wagaw,
S. J. Wittenberger, Ji Zhang, J. Am. Chem. Soc. 2002, 124,
13097–13105.
1
IIIi: Yield: 18.4%. UV kmax: 298nm. Mp.: 158-1628C (dec.). H-
NMR (D2O) d 1.11 (d, 3H, J = 6.9 Hz), 1.18 (d, 3H, J = 6.3 Hz), 1.23 (d,
1H, J = 6.7 Hz), 2.01–2.03 (m, 1H), 2.79–2.84 (m, 1H), 3.31–3.36
(m, 2H), 3.49–3.51 (m, 2H), 3.81 (s, 3H), 4.07–4.11 (m, 2H), 4.15 (t,
[9] D. H. Shih, F. L. Baker, B. G. Christensen, Heterocycles
1984, 21, 29–40.
i 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com