Synthesis and?in?vitro activity of?a?series 1β-methylcarbapenem derivatives

Article abstract of DOI:10.1016/j.ejmech.2006.05.003

The synthesis of a new series of 1β-methylcarbapenems having pyrrolidine and piperidine 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 p

Full text of DOI:10.1016/j.ejmech.2006.05.003

European Journal of Medicinal Chemistry 41 (2006) 1201–1209
http://france.elsevier.com/direct/ejmech
Short communication
Synthesis and in vitro activity of a series 1β-methylcarbapenem derivatives
H.C. Jeon b, J.-W. Kim a, J.H. Hong c, J.-H. Cho a, C.-H. Oh a,*
a Medicinal Chemistry Research Center, Korea Institute of Science and Technology, 39-1 Awolgok-dong, Seongbuk-gu, Seoul 130-650, Korea
b Department of Chemistry, Hanyang University, Seoul, Korea
c College of Pharmacy, Chosun University, Kwangju 501-759, Korea
Received in revised form 24 April 2006; accepted 4 May 2006
Available online 22 June 2006
Abstract
The synthesis of a new series of 1β-methylcarbapenems having pyrrolidine and piperidine 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 investi-
gated. A particular compound (IIIb) having hydroxypyrrolidine moiety showed the most potent antibacterial activity.
© 2006 Elsevier Masson SAS. All rights reserved.
Keywords: 1β-Methylcarbapenems; Antibacterial activity; Substituent effects
1. Introduction
In this paper, we described the synthesis and structure–
activity relationships of the l β-methylcarbapenems having 5′-
piperidine and pyrrolidine derivatives substituted pyrrolidin-3′-
ylthio group as C-2 side chain and our approach to improve the
antibacterial activity of the carbapenems is discussed.
Carbapenems are one of the most potent types of antibacter-
ial agents and are among those used as last resort against infec-
tions in the clinical field. Three carbapenems, imipenem [1,2],
meropenem [3] and ertapenem [4] have been marketed so far.
In particular, since it was revealed that 1β-methylcarbapenems
showed not only a broad antibacterial spectrum against both
Gram-positive and Gram-negative bacteria but also high stabi-
lity to human renal DHP-I [5,6]. The carbapenem 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. At present, several carbape-
nem derivatives such as S-4661 [8], BO-2727 [9] and E-1010
[10] are under clinical or preclinical studies since the launch of
meropenem.
2. Results and discussions
2.1. Chemistry
Our general synthetic route leading to new carbapenems
involved the preparation of appropriately protected thiols con-
taining pyrrolidine ring as a side chain and subsequent cou-
pling reaction with the carbapenem diphenylphosphates, fol-
lowed by deprotection of the resulting protected carbapenems
in a usual manner.
The β-ketoester 3 was prepared in three steps from glycine
ester and ethyl acrylate using Dieckmann condensation method
[16]. The intermediate 4 was obtained from decarboxylation of
3 with 10% hydrochloric acid [17], which was deprotected by
hydrogenation, respectively, in the presence of palladium car-
bon to provide the key compounds 5 and 6 (Scheme 1) [18].
The amides 8 and 9 were obtained by treatment of car-
boxylic acid 7 with β-keto ester amine 5 and 6 using oxalyl
chloride. The amides 8 and 9 were converted to the hydroxy
compounds 10 and 11 by treatment of sodium borohydride in
THF. Preparation of the oximes 12 and 13, and methoxyimino
We were also interested in this pyrrolidin-3-ylthio group
and reported that the carbapenem compounds which have a
pyrrolidin-3-ylthio group at the C-2 position in the carbapenem
skeleton are noted for their broad and potent antibacterial activ-
ity, and a large number of derivatives have been synthesized
and investigated [11–15].
* Corresponding author. Fax: +82 2 958 5189.
E-mail address: choh@kist.re.kr (C.-H. Oh).
0223-5234/$ - see front matter © 2006 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.05.003

1202
H.C. Jeon et al. / European Journal of Medicinal Chemistry 41 (2006) 1201–1209
compounds 14 and 15 were accomplished by treatment of the
amides 8 and 9 with hydroxyl and methoxyl amine. Deprotec-
tion of the trityl group to mercaptans Ia–g was achieved by
treatment of 9–15 with trifluoroacetic acid in the presence of
triethylsilane (Scheme 2).
tion with sodium hydride to give ethyl-N-benzyl-4-oxo-piperi-
dinecarboxylate (18) in moderate yield [19].
The compounds 20 and 21 were prepared from 18 and 19
by a similar manner as that described for the preparation of 5
and 6 (Scheme 3).
The reaction of benzylamine with excess of ethylacrylate in
the presence of triethylamine gave 17 of bis-addition in excel-
lent yield. Compound 17 was subjected to Dieckmann cycliza-
The treatment of the acid 7 with piperidine moiety 20 and
21 using oxalyl chloride gave the amides 22 and 23, which
were successfully converted into the derivatives 24–29, using
Scheme 1.
Scheme 2.
Scheme 3.

H.C. Jeon et al. / European Journal of Medicinal Chemistry 41 (2006) 1201–1209
1203
Scheme 4.
Scheme 5.
Scheme 6.
the same procedure as described for the preparation of 10–15
2.2. Biological studies
(Scheme 4).
Finally, the reaction of 30 with thiols (Ia–n) in the presence
of diisopropylethylamine gave the corresponding 2-substituted
carbapenems (IIa–n). Deprotection of these compounds by
treatment of tetrakis(triphenylphosphine)palladium(0) and tri-
butyltin hydride gave the crude products, which were purified
by HP-20 column to give the pure carbapenems (IIIa–n)
(Schemes 5 and 6).
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–1 with the same broth and inocu-
lated with an inoculating device onto agar containing serial two-
fold dilutions of the test compounds. Organisms were incubated
at 37 °C for 18–20 hours. The MICs of a compound were
defined as the lowest concentration that visibly inhibited growth.

1204
H.C. Jeon et al. / European Journal of Medicinal Chemistry 41 (2006) 1201–1209
The in vitro antibacterial activities of the new carbapenems
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 Staphylococcus aureus, Escherchia coil,
Klebsiella pneumonise, Enterobacter cloacae and Serratia
marcescens, IIIb was 2–5 times more active than the compared
meropenem and imipenem.
(IIIa–n) prepared above against Gram-positive and -negative
bacteria are listed in Tables 1 and 2. For comparison, the
MIC values of imipenem and meropenem are also listed. All
compounds displayed superior or similar antibacterial activities
against Gram-positive to meropenem, and Gram-negative bac-
teria to imipenem.
As to the substituent of the C-5 on the pyrrolidine side
chain, pyrrolidine moieties (IIIa–g) were generally more
potent than the piperidine moieties (IIIh–n). Introduction of
ester group (IIIa, IIIc, IIIe, IIIh, IIIj and IIIl) led to signifi-
cantly lowered antibacterial activity against Gram-positive and
Gram-negative bacteria compared to non-ester group (IIIb,
IIId, IIIf, IIIi, IIIk and IIIm). The effects of substituent on
the pyrrolidine and piperidine ring were investigated. The com-
pounds (IIIa, IIIb, IIIh and IIIi) having the hydroxy group
were generally more potent than the oxime and methoxy imine
groups. As a result, among them, compound IIIb having
hydroxypyrrolidine moiety showed the most potent antibacter-
ial activity.
3. Experimental
Melting point (m.p.): Thomas Hoover apparatus, uncor-
rected. UV spectra: Hewlett Packard 8451A UV–vis spectro-
photometer. IR spectra: Perkin Elmer 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.
3.1. (2S,4S)-2-[(4-oxo-3-ethoxycarbonypyrrolidinyl)
carbonyl]-4-tritylthio-1-(allyloxycarbon yl)pyrrolidine (8)
Comparative in vitro activities of IIIb, meropenem, and
imipenem against 40 bacterial strains are summarized in
Table 3. The selected carbapenem IIIb possessed excellent in
To a solution of 7 (2.0 g, 4.2 mmol) in dry CH2Cl2 (20 ml)
was added drop-wise oxalyl chloride (3.8 ml, 42.0 mmol) and
Table 1
In vitro antibacterial activity(MIC, μg ml–1) of the carbapenem derivatives(IIIa–g)
Strains
IIIa
1.56
0.20
6.25
0.01
0.01
0.02
6.25
0.01
0.02
0.02
0.01
0.02
12.5
25.0
IIIb
0.20
0.20
6.25
< 0.01
0.01
< 0.01
3.12
0.01
0.01
0.05
0.01
0.01
6.25
3.12
IIIc
12.5
0.80
25.0
0.04
0.20
0.04
12.5
0.10
0.10
0.20
0.20
0.20
50.0
50.0
IIId
12.5
0.20
12.5
0.02
0.10
0.04
3.12
0.02
0.10
0.04
0.04
0.10
12.5
3.12
IIIe
6.25
0.80
12.5
0.04
0.04
0.02
12.5
0.10
0.20
0.20
0.10
0.20
50.0
25.0
IIIf
IIIg
12.5
0.80
12.5
0.04
0.10
0.04
12.5
0.10
0.10
0.10
0.05
0.10
12.5
6.25
MPMa
6.25
0.10
12.5
0.01
0.04
0.01
3.12
0.04
0.02
0.02
0.02
0.04
6.25
3.12
IPMb
1.56
0.02
1.56
< 0.01
0.01
< 0.01
6.25
0.20
0.80
0.40
0.80
0.80
12.5
3.12
Staphylococcus aureus 121
Coagulasen staphylococci
Enterococcus faecalis 234
Streptococcus pyogenes 98
Streptococcus agalaciae 32
Streptococcus pneumoniae
Haemophilus influenzae 12
Escherichia coli 04
Klebsiella pneumoniae 52
Citrobacter freundii 323
Enterobacter cloacae 34
Serratia marcescens 3349
Acinetobacter baumannii 2
Pseudomonas aeruginosa 5
12.5
0.80
12.5
0.02
0.04
0.01
6.25
0.10
0.10
0.10
0.10
0.10
50.0
25.0
a
Meropenem.
Imipenem.
b
Table 2
In vitro antibacterial activity (MIC, μg ml–1) of the carbapenem derivatives(IIIh–n)
Strains
IIIh
3.12
0.20
6.25
0.02
0.02
0.02
3.12
0.02
0.10
0.02
0.04
0.02
12.5
25.0
IIIi
IIIj
IIIk
6.25
0.40
12.5
0.02
0.02
0.04
6.25
0.02
0.10
0.04
0.04
0.04
12.5
12.5
IIIl
IIIm
6.25
0.10
6.25
0.01
0.02
< 0.01
3.12
0.10
0.10
0.10
0.10
0.10
50.0
12.5
IIIn
12.5
0.20
12.5
0.02
0.04
0.01
3.12
0.04
0.04
0.04
0.04
0.10
25.0
3.12
MPM
6.25
0.10
12.5
0.01
0.04
0.01
3.12
0.04
0.02
0.02
0.02
0.04
6.25
3.12
IPM
1.56
0.02
1.56
< 0.01
0.01
< 0.01
6.25
0.20
0.80
0.40
0.80
0.80
12.5
3.12
Staphylococcus aureus 121
Coagulasen staphylococci
Enterococcus faecalis 234
Streptococcus pyogenes 98
Streptococcus agalaciae 32
Streptococcus pneumoniae
Haemophilus influenzae 12
Escherichia coli 04
Klebsiella pneumoniae 52
Citrobacter freundii 323
Enterobacter cloacae 34
Serratia marcescens 3349
Acinetobacter baumannii 2
Pseudomonas aeruginosa 5
3.12
0.10
6.25
0.01
0.01
0.01
3.12
0.01
0.05
0.02
0.02
0.02
6.25
12.5
12.5
0.80
25.0
0.04
0.04
0.04
12.5
0.04
0.10
0.10
0.04
0.10
25.0
25.0
6.25
0.10
6.25
0.01
0.02
< 0.01
6.25
0.20
0.20
0.10
0.10
0.40
50.0
25.0

H.C. Jeon et al. / European Journal of Medicinal Chemistry 41 (2006) 1201–1209
1205
Table 3
comparative in vitro antibacterial activity of IIIb, meropenem and imipenem against 40 strains (MIC, μg ml–1
)
Organism
IIIb
0.01
0.01
0.01
0.01
< 0.01
0.02
0.10
0.02
0.04
1.56
0.80
0.80
0.80
0.40
0.02
0.02
0.04
0.02
0.04
0.02
IPM
0.01
0.01
< 0.01
0.01
< 0.01
0.01
0.10
0.02
0.02
0.80
0.80
0.80
0.80
0.80
0.10
0.10
0.10
0.04
0.20
0.10
MPM
0.10
0.10
0.04
0.04
0.01
0.04
0.80
0.04
0.04
0.40
0.80
0.40
0.20
0.40
0.04
0.02
0.04
0.02
0.04
0.04
Organism
IIIb
0.10
0.20
0.20
0.03
0.10
0.10
0.02
0.02
0.01
0.02
0.02
0.10
0.20
0.20
0.40
0.40
0.40
0.05
0.01
0.01
IPM
0.10
0.40
0.40
0.04
0.20
0.20
0.20
0.10
0.20
0.20
0.40
0.80
0.20
0.10
0.10
0.20
0.20
<0.01
0.02
<0.01
MPM
0.02
0.04
0.04
0.01
0.10
0.02
0.04
0.04
0.02
0.04
0.04
0.20
0.10
0.10
0.10
0.10
0.04
0.04
0.04
0.02
Staphylococcus aureus giorgio
Staphylococcus aureus 209P
Staphylococcus aureus 503
Micrococcus luteus ATCC 9341
Streptococcus facium 77A
Streptococcus agalctiae B
Streptococcus durans D
Bacillus subtilis ATCC 6633
Bacillus megatherium
Pseudomonas aeruginosa 9027
Pseudomonas aeruginosa 77/2
Pseudomonas aeruginosa 110/2
Pseudomonas aeruginosa 880/2
Pseudomonas cepacia
Salmonella paratyphi A
Salmonella typhimurium
Salmonella oranienberg
Salmonella typhi
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
Proteus rettgeri 936
Proteus rettgeri 937
Pasteurella multocida
Escherichia coli 086
Escherichia coli 0114
Escherichia coli 0126
Escherichia coli V6311/65
Escherichia coli TEM
Corynebacterium diphtheriae
Corynebacterium pyogenes
Escherichia coli 1507
was stirred for 2 h at room temperature. The mixture was eva-
porated under reduced pressure. To an ice-cold solution of 5
(0.75 g, 4.2 mmol) and triethylamine (1.4 ml, 10.6 mmol) in
dry CH2Cl2 (20 ml) was slowly added to the above solution at
0 °C and mixture was stirred for 30 min at room temperature.
The mixture was diluted with H2O (50 ml) and CH2Cl2
(100 ml). The organic layer was dried over anhydrous
Na2SO4, concentrated, and the resulting residue was purified
by silica gel column chromatography (EtOAc/hexane = 1:3)
acid, and then extracted with ethyl acetate. Evaporation of the
solvent in vacuo gave a crude residue, which was purified by
silica gel column chromatography (EtOAc/hexane = 1:2) to
give 10 (1.2 g, 78.0%) as a pale yellow oil.
1H NMR (CDCl3): δ 1.24–1.32 (m, 3H), 1.82–2.08 (m, 2H),
2.74–2.79 (m, 1H), 2.95–3.08 (m, 2H), 3.15–3.19 (m, 1H),
3.54–3.66 (m, 2H), 3.75–3.82 (m, 1H), 3.83–4.07 (m, 1H),
4.14–4.21 (m, 3H), 4.39–4.55 (m, 3H), 5.14–5.26 (m, 2H),
5.79–5.89 (m, 1H), 7.20–7.33 (m, 9H), 7.46 (d, 6H,
J = 7.5 Hz).
1
to give 8 (2.1 g, 82.5%). H NMR (CDCl3): δ 1.27–1.36 (m,
3H), 1.45 (bs, 1H), 1.78–1.90 (m, 1H), 1.97–2.06 (m, 1H),
2.41–2.65 (m, 2H), 3.05–3.31 (m, 2H), 3.70–3.82 (m, 2H),
4.12–4.31 (m, 3H), 4.41–4.53 (m, 3H), 5.20–5.31 (m, 2H),
5.82–5.90 (m, 1H), 7.23–7.37 (m, 9H), 7.46 (d, 6H,
J = 7.2 Hz). 13C NMR (300 MHz, CDCl3): δ 14.2, 29.4,
29.6, 31.9, 36.2, 37.2, 51.3, 57.5, 60.6, 62.4, 67.3, 117.2,
126.9, 128.1, 129.5, 132.7, 144.6, 153.2, 170.2, 171.6, 206.2.
The synthesis of compound 9 was carried out by the same
procedure as described for the preparation of 8 using com-
pound 6.
The synthesis of compound 11 was carried out by the same
procedure as described for the preparation of 10 using com-
pound 9.
1
11: H NMR (CDCl3): δ 1.67–1.78 (m, 1H), 1.90–1.98 (m,
1H), 2.31–2.51 (m, 3H), 2.59–2.98 (m, 2H), 3.13–3.28 (m,
2H), 3.49–3.64 (m, 2H), 4.05–4.14 (m, 1H), 4.39–4.57 (m,
3H), 5.10–5.23 (m, 2H), 5.83–5.93 (m, 1H), 7.20–7.33 (m,
9H), 7.47 (d, 6H, J = 7.8 Hz). 13C NMR (300 MHz, CDCl3):
δ 29.6, 32.6, 34.1, 41.7, 52.2, 53.5, 54.3, 57.0, 67.2, 69.0,
117.4, 126.9, 128.1, 130.0, 132.6, 114.6, 153.4, 171.2.
1
9: H NMR (CDCl3): δ 1.76–2.03 (m, 2H), 2.52–2.67 (m,
2H), 2.70–2.82 (m, 1H), 3.13 (d, 2H, J = 9.0 Hz), 3.60–3.74
(m, 1H), 3.77–3.87 (m, 1H), 3.91–4.04 (m, 2H), 4.07–4.14 (m,
1H), 4.40–4.60 (m, 2H), 5.11–5.26 (m, 2H), 5.71–5.93 (m,
1H), 7.20–7.32 (m, 9H), 7.46 (d, 6H, J = 7.5 Hz).
3.3. (2S,4S)-2-[(4-hydroxyimino-3-ethoxycarbonypyrrolidinyl)
carbonyl]-4-tritylthio-1-(allyl oxycarbonyl)pyrrolidine (12)
To a stirred solution of 8 (1.5 g, 2.5 mmol) in EtOH (20 ml)
was added drop-wise 50% aqueous hydroxylamine (0.18 ml,
2.9 mmol) and was stirred for 7 h at 50 °C. The reaction mix-
ture was diluted with ethyl acetate (50 ml) and water (50 ml),
and then the organic layer was dried over anhydrous Na2SO4.
Evaporation of the solvent in vacuo gave a crude residue,
which was purified by silica gel column chromatography
(EtOAc/hexane = 1:1) to give 12 (1.3 g, 81.2%) as a pale yel-
low oil. 1H NMR (CDCl3): δ 1.22–1.31 (m, 4H), 1.73–1.94 (m,
1H), 2.74–2.86 (m, 1H), 2.99–3.11 (m, 2H), 3.72–4.05 (m,
3H), 4.10–4.27 (m, 4H), 4.47–4.61 (m, 3H), 5.11–5.23 (m,
2H), 5.71–5.93 (m, 1H), 7.20–7.33 (m, 9H), 7.47 (d, 6H,
13C NMR (300 MHz, CDCl3): δ 35.7, 36.2, 37.2, 43.3,
52.4, 53.5, 55.7, 66.0, 67.3, 117.3, 127.0, 128.0, 129.5,
132.6, 144.6, 153.1, 170.8, 209.8.
3.2. (2S,4S)-2-[(4-hydroxy-3-ethoxycarbonypyrrolidinyl)
carbonyl]-4-tritylthio-1-(allyloxycar bonyl)pyrrolidine (10)
To a solution of 8 (1.5 g, 2.5 mmol) in THF (30 ml) was
added slowly NaBH4 (0.18 g, 4.9 mmol) at 0 °C and was stir-
red for 2 h at room temperature. The reaction mixture was
poured into cold ice water, acidified to pH 4–5 with acetic

1206
H.C. Jeon et al. / European Journal of Medicinal Chemistry 41 (2006) 1201–1209
J = 7.5 Hz). 13C NMR (300 MHz, CDCl3): δ 14.1, 21.1, 36.0,
44.8, 47.9, 52.2, 53.5, 56.4, 60.5, 61.9, 67.3, 117.3, 127.0,
128.1, 129.5, 132.6, 144.6, 154.4, 169.4, 170.0, 170.2.
The synthesis of compound 13 was carried out by the same
procedure as described for the preparation of 12 using com-
pound 9.
tion at 0 °C and was the mixture stirred for 30 min at room
temperature. The mixture was diluted with H2O (50 ml) and
CH2Cl2 (100 ml). The organic layer was dried over anhydrous
Na2SO4, concentrated, and the resulting residue was purified
by silica gel column chromatography (EtOAc/hexane = 1:3)
1
to give 22 (2.2 g, 82.5%). H NMR (CDCl3): δ 1.21–1.37
1
(m, 4H), 1.43–2.01 (m, 2H), 2.33–2.34 (d, 2H, J = 4.5 Hz),
2.80–2.86 (m, 1H), 3.14–3.25 (m, 2H), 3.49–3.53 (m, 2H),
4.15–4.30 (m, 4H), 4.38–4.50 (m, 3H), 5.06–5.30 (m, 2H),
5.80–5.91 (m, 1H), 7.20–7.38 (m, 9H), 7.45 (d, 6H,
J = 7.6 Hz). 13C NMR (300 MHz, CDCl3): δ 36.7, 37.8,
41.7, 44.2, 55.0, 53.5, 55.4, 67.2, 117.2, 126.9, 128.0, 129.5,
132.7, 144.6, 154.1, 170.5, 206.8.
13: H NMR (CDCl3): δ 1.75–1.86 (m, 1H), 1.98–2.05 (m,
1H), 2.65 (t, 1H, J = 7.2 Hz), 2.75–2.79 (m, 2H), 3.10–3.14
(m, 1H), 3.19–3.53 (m, 1H), 3.60–3.64 (m, 1H), 3.84–4.05
(m, 1H), 4.14–4.30 (m, 2H), 4.37–4.53 (m, 3H), 5.10–5.27
(m, 2H), 5.70–5.93 (m, 1H), 7.03–7.32 (m, 9H), 7.47 (d, 6H,
J = 7.5 Hz). 13C NMR (300 MHz, CDCl3): δ 27.1, 29.0, 36.0,
45.8, 52.2, 53.5, 56.5, 57.1, 67.3, 117.3, 127.0, 128.1, 129.5,
132.5, 114.6, 154.4, 158.7, 170.4.
The synthesis of compound 23 was carried out by the same
procedure as described for the preparation of 22 using com-
pound 21.
3.4. (2S,4S)-2-[(4-methoxyimino-3-ethoxycarbonypyrrolidinyl)
carbonyl]-4-tritylthio-1-(allyl oxycarbonyl)pyrrolidine (14)
1
23: H NMR (CDCl3): δ 1.62–1.77 (m, 2H), 1.88–1.94 (m,
1H), 2.31–2.49 (m, 3H), 2.78–2.84 (m, 2H), 3.12–3.27 (m,
2H), 3.49–3.63 (m, 2H), 3.81–3.95 (m, 1H), 4.38–4.52 (m,
3H), 5.09–5.30 (m, 2H), 5.83–5.92 (m, 1H), 7.20–7.36 (m,
9H), 7.46 (d, 6H, J = 7.5 Hz). 13C NMR (300 MHz, CDCl3):
δ 36.7, 37.8, 41.7, 44.2, 55.0, 53.5, 55.4, 67.2, 117.2, 126.9,
128.0, 129.5, 132.7, 144.6, 154.1, 170.5, 206.8.
To a solution of 8 (1.0 g, 1.6 mmol) in dry pyridine (20 ml)
was added drop-wise methoxylamine hydrochloride (0.52 ml,
2.9 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
vacuo to give a residue, which was purified by silica gel col-
umn chromatography (EtOAc/hexane = 1:1) to give 14 (0.78 g,
The synthesis of compounds 24 and 25 was carried out by
the same procedure as described for the preparation of 10 using
compounds 20 and 21.
1
1
76.2%) as a pale yellow oil. H NMR (CDCl3): δ 1.25–1.34
24: H NMR (CDCl3): δ 1.22–1.37 (m, 6H), 1.49–1.61 (m,
(m, 4H), 1.73–1.88 (m, 2H), 2.00–2.09 (m, 1H), 2.71–2.80
(m, 1H), 3.06–3.13 (m, 1H), 3.71–3.82 (m, 1H), 3.89–3.95
(m, 4H), 4.11–4.27 (m, 5H), 4.45–4.51 (m, 2H), 5.10–5.22
(m, 1H), 5.27 (d, 1H, J = 6.8 Hz), 5.80–5.91 (m, 1H), 7.20–
7.32 (m, 9H), 7.46 (d, 6H, J = 7.5 Hz). 13C NMR (300 MHz,
CDCl3): δ 14.1, 36.1, 37.1, 44.8, 47.7, 52.2, 53.5, 57.0, 62.0,
65.8, 67.3, 117.1, 126.9, 128.1, 129.5, 132.6, 144.6, 155.4,
164.6, 172.0, 173.2.
1H), 1.72–1.97 (m, 2H), 2.73–2.81 (m, 1H), 3.07–3.27 (m,
2H), 3.41–3.52 (m, 1H), 3.41–3.52 (m, 1H), 3.54–3.69 (m,
1H), 4.08–4.26 (m, 2H), 4.42–4.52 (m, 4H), 5.10–5.27 (m,
2H), 5.81–5.92 (m, 1H), 7.20–7.32 (m, 9H), 7.45 (d, 6H,
J = 7.5 Hz). 13C NMR (300 MHz, CDCl3): δ 14.1, 21.1,
22.7, 29.7, 31.5, 31.7, 37.5, 45.6, 52.4, 55.5, 60.4, 61.5,
67.2, 117.0, 126.9, 128.1, 129.5, 132.8, 144.6, 154.0, 169.5,
172.1.
1
The synthesis of compound 15 was carried out by the same
procedure as described for the preparation of 14 using com-
pound 9.
25: H NMR (CDCl3): δ 1.42–1.52 (m, 1H), 1.55–1.66 (m,
2H), 1.75–1.98 (m, 4H), 2.75–2.81 (m, 1H), 3.07–3.27 (m,
3H), 3.54–3.59 (m, 2H), 3.92–4.00 (m, 2H), 4.33–4.58 (m,
2H), 5.12–5.27 (m, 2H), 5.82–5.93 (m, 1H), 7.20–7.33 (m,
9H), 7.46 (d, 6H, J = 7.5 Hz). 13C NMR (300 MHz, CDCl3):
δ 19.4, 29.7, 33.8, 36.6, 42.4, 52.0, 53.4, 55.8, 65.8, 67.2,
117.1, 126.9, 128.1, 129.5, 132.8, 144.6, 154.0, 176.4.
The synthesis of compounds 26 and 27 was carried out by
the same procedure as described for the preparation of 12 using
compounds 20 and 21.
1
15: H NMR (CDCl3): δ 1.84 (t, 1H, J = 10.5 Hz), 1.90–
2.05 (m, 1H), 2.67–2.79 (m, 3H), 3.12 (d, 1H, J = 8.1 Hz),
3.29–3.58 (m, 1H), 3.64–3.68 (m, 1H), 3.88 (s, 3H), 3.95–
4.00 (m, 1H), 4.07–4.22 (m, 2H), 4.38–4.54 (m, 3H), 5.11–
5.28 (m, 2H), 5.71–5.93 (m, 1H), 7.20–7.32 (m, 9H), 7.46 (d,
6H, J = 6.9 Hz). 13C NMR (300 MHz, CDCl3): δ 26.5, 27.2,
36.1, 41.7, 44.4, 46.1, 47.8, 52.0, 62.1, 67.3, 117.2, 126.9,
128.1, 129.5, 132.7, 144.6, 154.1, 165.3, 173.2.
1
26: H NMR (CDCl3): δ 1.23–1.39 (m, 6H), 1.53–1.65 (m,
1H), 1.72–1.99 (m, 2H), 2.73–2.81 (m, 1H), 3.07–3.27 (m,
2H), 3.41–3.52 (m, 1H), 3.41–3.52 (m, 1H), 3.54–3.69 (m,
1H), 4.08–4.26 (m, 1H), 4.42–4.52 (m, 4H), 5.10–5.27 (m,
2H), 5.81–5.92 (m, 1H), 7.20–7.32 (m, 9H), 7.45 (d, 6H,
J = 7.5 Hz). 13C NMR (300 MHz, CDCl3): δ 14.1, 21.1,
22.7, 29.7, 31.5, 31.7, 37.5, 45.6, 52.4, 60.4, 61.5, 67.2,
117.0, 126.9, 128.1, 129.5, 132.8, 144.6, 154.0, 169.5, 172.1.
27: 1H NMR (CDCl3): δ 1.65 (s, 4H), 2.32 (d, 1H,
J = 6.0 Hz), 2.47–2.69 (m, 2H), 2.73–2.85 (m, 1H), 3.10–
3.29 (m, 2H), 3.32–3.47 (m, 1H), 3.55–3.60 (m, 2H), 3.72–
3.5. (2S,4S)-2-[(4-oxo-3-ethoxycarbonypiperidinyl)carbonyl]-
4-tritylthio-1-(allyloxycarbonyl) pyrrolidine (22)
To a solution of 7 (2.0 g, 4.2 mmol) in dry CH2Cl2 (20 ml)
was added drop-wise oxalyl chloride (3.8 ml, 42.0 mmol) and
was stirred for 2 h at room temperature. The mixture was eva-
porated under reduced pressure. To an ice-cold solution of 20
(0.72 g, 4.2 mmol) and triethylamine (1.4 ml, 10.5 mmol) in
dry CH2Cl2 (20 ml) was slowly added the prepared above solu-

H.C. Jeon et al. / European Journal of Medicinal Chemistry 41 (2006) 1201–1209
1207
3.87 (m, 1H), 4.32–4.57 (m, 2H), 5.19–5.30 (m, 2H), 5.83–
5.92 (m, 1H), 7.20–7.32 (m, 9H), 7.45 (d, 6H, J = 7.5 Hz).
13C NMR (300 MHz, CDCl3): δ 25.2, 25.8, 30.6, 31.4, 36.7,
45.1, 52.0, 52.3, 61.4, 67.2, 117.1, 126.9, 128.0, 129.5, 132.8,
114.6, 153.3, 169.9, 171.3.
IIb: Yield 24.8%. 1H NMR (CDCl3): δ 1.25 (d, 3H,
J = 8.1 Hz), 1.36 (d, 3H, J = 5.9 Hz), 1.63 (bs, 2H), 2.19 (bs,
1H), 2.65 (bs, 1H), 3.25–3.28 (m, 1H), 3.32–3.55 (m, 4H),
3.58–3.63 (m, 2H), 3.77 (d, 1H, J = 12.3 Hz), 3.89–4.10 (m,
1H), 4.23–4.27 (m, 2H), 4.49–4.59 (m, 4H), 4.72 (dd, 1H,
J = 5.4 and 5.8 Hz), 4.82 (dd, 1H, J = 5.7 and 5.8 Hz), 5.22–
5.34 (m, 3H), 5.43 and 5.48 (2s, 1H), 5.92–6.03 (m, 2H).
The synthesis of compounds 28 and 29 was carried out by
the same procedure as described for the preparation of 14 using
compounds 20 and 21.
1
IIc: Yield 29.3%. H NMR (CDCl3): δ 1.27–1.34 (m, 6H),
1
28: H NMR (CDCl3): δ 1.22 (m, 3H), 1.62 (s, 3H), 1.86–
1.36 (d, 3H, J = 4.3 Hz), 2.02–2.06 (m, 2H), 2.34–2.39 (m,
1H), 2.48–2.80 (m, 2H), 3.32–3.52 (m, 2H), 3.96–4.12 (m,
2H), 4.24–4.46 (m, 5H), 4.59 (bs, 4H), 4.72 (dd, 1H, J = 5.8
and 5.3 Hz), 4.81 (dd, 1H, J = 5.8 and 5.3 Hz), 5.23–5.35 (m,
4H), 5.43 and 5.49 (2s, 1H), 5.89–6.02 (m, 2H).
2.08 (m, 1H), 2.38–2.56 (m, 2H), 3.02–3.42 (m, 3H), 3.45–
3.55 (m, 1H), 3.88 (d, 3H, J = 11.1 Hz), 4.08–4.22 (m, 3H),
4.25–4.42 (m, 2H), 4.46–4.55 (m, 2H), 5.11–5.29 (m, 2H),
5.79–5.87 (m, 1H), 7.19–7.32 (m, 9H), 7.44 (d, 6H,
J = 7.5 Hz). 13C NMR (300 MHz, CDCl3): δ 14.2, 24.0,
25.6, 29.6, 29.7, 44.4, 46.2, 51.9, 52.2, 55.7, 56.0, 61.7,
61.8, 67.2, 117.0, 126.9, 128.1, 132.7, 154.0, 170.2, 171.4.
IId: Yield 33.8%. 1H NMR (CDCl3): δ 1.26 (d, 3H,
J = 7.5 Hz), 1.37 (d, 3H, J = 6.2 Hz), 2.00–2.18 (m, 2H),
2.54–2.66 (m, 1H), 2.73–2.85 (m, 1H), 2.96–3.08 (m, 1H),
3.25 (d, 1H J = 5.1 Hz), 3.34–3.40 (m, 1H), 3.45–3.51 (m,
2H), 3.52–3.75 (m, 2H), 3.73 (s, 1H), 4.14–4.30 (m, 2H),
4.58 (bs, 4H), 4.70 (dd, 1H, J = 5.7 and 6.0 Hz), 4.82 (dd,
1H, J = 5.4 and 5.8 Hz), 5.22–5.29 (m, 3H), 5.42 and 5.48
(2s, 1H), 5.89–6.01 (m, 2H).
1
29: H NMR (CDCl3): δ 1.60–1.70 (m, 5H), 2.32–2.35 (m,
1H), 2.71–2.88 (m, 1H), 3.14–3.25 (m, 2H), 3.51–3.65 (m,
5H), 3.85 (d, 3H, J = 3.3 Hz), 4.39–4.53 (m, 2H), 5.10–5.23
(m, 2H), 5.82–5.93 (m, 1H), 7.21–7.33 (m, 9H), 7.47 (d, 6H,
J = 7.5 Hz). 13C NMR (300 MHz, CDCl3): δ 25.2, 25.8, 30.6,
31.4, 36.7, 45.1, 52.0, 52.3, 55.7, 61.4, 67.2, 117.1, 126.9,
128.0, 129.5, 132.8, 114.6, 153.3, 169.9, 171.3.
1
IIe: Yield 26.9%. H NMR (CDCl3): δ 1.25–1.33 (m, 6H),
1.37 (d, 3H, J = 6.2 Hz), 1.67 (bs, 2H), 2.00–2.09 (m, 2H),
2.65 (m, 1H), 3.29–3.39 (m, 1H), 3.41–3.53 (m, 1H), 3.55–
2.72 (m, 1H), 3.91 (m, 4H), 4.11–4.38 (m, 6H), 4.39–4.66
(m, 4H), 4.66–4.71 (m, 1H), 4.81 (dd, 1H, J = 3.3 and
10.2 Hz), 5.17–5.32 (m, 3H), 5.42 and 5.46 (2s, 1H), 5.88–
5.99 (m, 2H).
3.6. Allyl(1R,5S,6S)-6-[(1R)-hydroxyethyl]-2-[5-(4-
hydroxyimino-3-ethoxycarbonypyrrolidinyl)carbonyl]-1-
(allyloxycarbonyl)pyrrolidin-3-ylthio]-1-methylcarbapen-2-em-
3-carboxylate (IIa)
IIf: Yield 32.1%. 1H NMR (CDCl3): δ 1.27 (d, 3H,
J = 7.2 Hz), 1.36 (d, 3H, J = 5.8 Hz), 1.82 (bs, 2H), 2.58–
2.67 (m, 1H), 2.72–2.81 (m, 1H), 2.86–2.94 (m, 1H), 3.25–
3.29 (m, 1H), 3.37–3.50 (m, 2H), 3.64–3.82 (m, 2H), 3.88–
3.90 (m, 3H), 4.15–4.25 (m, 4H), 4.39–4.57 (m, 4H), 4.70
(dd, 1H, J = 5.4 and 5.2 Hz), 4.82 (dd, 1H, J = 5.2 and
5.3 Hz), 5.17–5.29 (m, 3H), 5.42 and 5.48 (2s, 1H), 5.88–
5.98 (m, 2H).
To a solution of 10 (0.61 g, 1.0 mmol) in CH2Cl2 (3 ml)
was added drop-wise triethylsilane (0.20 ml, 1.2 mmol) at
5 °C, and then TFA (1.2 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, brine. The organic layer was con-
centrated in vacuo to give a residue (Ia), which was used with-
out further purification. A solution of allyl (1R,5S,6S)-2-
(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcar-
bapen-2-em-3-carb-oxylate (30, 0.60 g, 1.2 mmol) in CH3CN
(10 ml) was cooled to 0 °C under N2. To this solution was
added diisopropylethyl amine (0.13 g, 1.0 mmol) and a solu-
tion 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 = 3:1) to give
IIg: Yield 29.6%. 1H NMR (CDCl3): δ 1.25 (d, 3H,
J = 6.1 Hz), 1.37 (d, 3H, J = 4.5 Hz), 2.07–2.17 (m, 2H),
2.62 (bs, 2H), 2.72 (bs, 1H), 3.36 (t, 1H, J = 5.7 Hz), 3.48 (t,
1H, J = 7.8 Hz), 3.64 (bs, 1H), 3.78–3.96 (m, 2H), 3.98–4.09
(m, 2H), 4.24–4.31 (m, 2H), 4.49–4.67 (m, 4H), 4.70 (dd, 1H,
J = 5.2 and, 5.0 Hz), 4.82 (dd, 1H, J = 5.1 and 5.2 Hz), 5.19–
5.23 (m, 3H), 5.43 and 5.47 (2s, 1H), 5.90–6.00 (m, 2H).
1
IIh: Yield 34.2%. H NMR (CDCl3): δ 1.25–1.33 (m, 6H),
1.36 (d, 3H, J = 5.6 Hz), 2.00–2.19 (m, 2H), 2.61–2.74 (m,
3H), 3.10–3.30 (m, 3H), 3.32–3.49 (m, 4H), 3.55–3.66 (m,
2H), 4.16–4.27 (m, 3H), 4.35 (s, 1H), 4.38–4.60 (m, 4H),
4.72 (dd, 1H, J = 5.1 and 5.1 Hz), 4.83 (dd, 1H, J = 5.7 and
5.5 Hz), 5.21–5.35 (m, 3H), 5.42 and 5.48 (2s, 1H), 5.88–5.98
(m, 2H).
IIi: Yield 33.0%. 1H NMR (CDCl3): δ 1.17 (d, 3H,
J = 5.0 Hz), 1.26 (d, 3H, J = 6.3 Hz), 1.90 (bs, 4H), 2.69 (bs,
1H), 3.25 (d, 2H, J = 6.9 Hz), 3.33–3.48 (m, 3H), 3.56–3.85
(m, 2H), 3.98–4.16 (m, 3H), 4.23–4.26 (m, 2H), 4.58 (d, 4H,
J = 5.1 Hz), 4.70 (dd, 1H, J = 5.1 and 5.0 Hz), 4.82 (dd, 1H,
1
IIa (0.20 g, 33.3%) as a yellow amorphous solid. H NMR
(CDCl3): δ 1.25–1.31 (m, 6H), 1.36 (d, 3H, J = 4.3 Hz),
1.95–2.05 (m, 1H), 2.60–2.65 (bs, 1H), 2.95–3.06 (m, 1H),
3.24–3.28 (bs, 1H), 3.48–3.65 (m, 3H), 3.69–3.78 (m, 2H),
3.88–4.02 (m, 2H), 4.12–4.25 (m, 5H), 4.46–4.58 (m, 4H),
4.70 (dd, 1H, J = 5.7 and 5.8 Hz), 4.82 (dd, 1H, J = 5.4 and
5.5 Hz), 5.19–5.34 (m, 3H), 5.42 and 5.47 (2s, 1H), 5.87–6.04
(m, 2H).
The synthesis of compounds IIb–n were carried out by the
same procedure as described for the preparation of IIa.

1208
H.C. Jeon et al. / European Journal of Medicinal Chemistry 41 (2006) 1201–1209
J = 4.2 and 4.1 Hz), 5.21–5.35 (m, 3H), 5.42 and 5.47 (2s,
1H), 5.87–6.03 (m, 2H).
2H), 3.93–3.97 (m, 1H), 4.07–4.16 (m, 4H), 4.47–4.52 (m,
2H). IR (KBr): 3480, 1720, 1690, 1670 cm–1. HRMS (FAB)
Calcd. for C22H31N3O8S 497.1832, Found 497.1830.
1
IIj: Yield 30.8%. H NMR (CDCl3): δ 1.25–1.33 (m, 6H),
1.36 (d, 3H, J = 5.6 Hz), 1.90–2.10 (m, 2H), 2.18–2.30 (m,
1H), 2.54–2.81 (m, 1H), 2.83–3.15 (m, 1H), 3.17–3.28 (m,
1H), 3.41–3.51 (m, 5H), 3.87 (d, 5H, J = 6.6 Hz), 4.14–4.29
(m, 4H), 4.54 (d, 4H, J = 17.1 Hz), 4.69 (dd, 1H, J = 5.7 and
5.8 Hz), 4.83 (m, 1H, J = 5.4 and 5.1 Hz), 5.20–5.34 (m, 3H),
5.42 and 5.48 (2s, 1H), 5.86–6.00 (m, 2H).
The synthesis of compounds IIIb-n were carried out by the
same procedure as described for the preparation of IIIa.
IIIb: Yield 24.2%. UV λmax: 298 nm. m.p.: 115–122 °C
1
(dec.). H NMR (D2O): δ 1.10 (d, 3H, J = 7.2 Hz), 1.18 (d,
3H, J = 6.3 Hz), 1.80–2.12 (m, 4H), 2.95 (bs, 1H), 3.23–3.37
(m, 4H), 3.41–3.68 (m, 5H), 3.94 (t, 1H, J = 6.0 Hz), 4.12–
4.16 (m, 2H). IR (KBr): 3460, 1710, 1650 cm–1. HRMS
(FAB) Calcd. for C19H27N3O6S 425.1621, Found 425.1621.
IIIc: Yield 23.9%. UV λmax: 298 nm. m.p.: 120–125 °C
IIk: Yield 34.3%. 1H NMR (CDCl3): δ 1.17 (d, 3H,
J = 6.0 Hz), 1.29(d, 3H, J = 6.1 Hz), 1.56–1.79 (bs, 3H),
2.31–2.41 (m, 1H), 2.43–2.58 (m, 1H), 2.97–3.16 (m, 2H),
3.27 (s, 1H), 3.35–3.59 (m, 4H), 3.66–3.74 (m, 3H), 4.25 (d,
1H, J = 4.2 Hz), 4.60–4.62 (m, 4H), 4.68–4.74 (m, 1H), 4.84
(dd, 1H, J = 5.1 and 5.5 Hz), 5.20–5.31 (m, 3H), 5.43 and 5.49
(2s, 1H), 5.88–6.00 (m, 2H).
1
(dec.). H NMR (D2O): δ 1.13–1.23 (m, 6H), 1.32 (d, 3H,
J = 5.5 Hz), 1.91 (bs, 1H), 2.99 (bs, 1H), 3.18–3.38 (m, 3H),
3.56–3.73 (m, 1H), 3.74–3.88 (m, 1H), 3.90–4.07 (m, 1H),
4.08–4.34 (m, 4H), 4.35–4.54 (m, 2H), 4.55–4.61 (m, 1H),
5.39–5.45 (m, 2H). IR (KBr): 3460, 1740, 1710, 1660,
1610 cm–1. HRMS (FAB) Calcd. for C22H30N4O8S 510.1784,
Found 510.1780.
1
IIl: Yield 31.3%. H NMR (CDCl3): δ 1.18–1.27 (m, 6H),
1.33 (d, 3H, J = 5.6 Hz), 1.90–2.10 (m, 2H), 2.18–2.30 (m,
1H), 2.54–2.81 (m, 1H), 2.83–3.15 (m, 1H), 3.17–3.28 (m,
1H), 3.41–3.51 (m, 5H), 3.87 (d, 5H, J = 6.6 Hz), 4.14–4.29
(m, 4H), 4.54 (d, 4H, J = 17.1 Hz), 4.69 (dd, 1H, J = 5.7 and
5.8 Hz), 4.83 (m, 1H, J = 5.4 and 5.1 Hz), 5.20–5.34 (m, 3H),
5.42 and 5.48 (2s, 1H), 5.86–6.00 (m, 2H).
IIId: Yield 24.0%. UV λmax: 298 nm. m.p.: 128–134 °C
(dec.). 1H NMR (D2O): 1.09 (d, 3H, J = 5.4 Hz), 1.17 (d,
3H, J = 4.5 Hz), 1.79–1.99 (m, 1H), 2.66–2.70 (m, 1H),
2.74–2.78 (m, 1H), 2.95–2.99 (m, 1H), 3.23–3.29 (m, 1H),
3.31–3.47 (m, 2H), 3.49–3.56 (m, 1H), 3.58–3.72 (m, 3H),
3.73–3.84 (m, 2H), 3.95 (m, 1H), 4.07–4.17 (m, 2H). IR
(KBr): 3490, 1710, 1670, 1610 cm–1. HRMS (FAB) Calcd. for
C19H26N4O6S 438.1573, Found 438.1577.
IIm: Yield 31.5%. 1H NMR (CDCl3): δ 1.25 (d, 3H,
J = 4.2 Hz), 1.35 (d, 3H, J = 7.5 Hz), 1.91–2.04 (m, 2H),
2.40 (d, 3H, J = 4.2 Hz), 2.60–2.71 (m, 3H), 3.19–3.37 (m,
1H), 3.44–3.62 (m, 5H), 3.85 (d, 3H, J = 3.7 Hz), 3.92–4.19
(m, 2H), 4.49–4.60 (m, 4H), 4.73 (dd, 1H, J = 4.9 and
13.2 Hz), 4.80 (m, 1H, J = 3.8 and 12.1 Hz), 5.21–5.33 (m,
3H), 5.42 and 5.46 (2s, 1H), 5.92–6.00 (m, 2H).
1
IIIe: Yield 24.2%. UV λmax: 298 nm. H NMR (D2O): δ
1.09 (d, 3H, J = 5.3 Hz), 1.17 (d, 3H, J = 4.6 Hz), 1.80–1.97
(m, 1H), 2.86–3.09 (m, 2H), 1.25–1.32 (m, 3H), 3.19–3.42 (m,
2H), 3.47–3.60 (m, 1H), 3.61–3.72 (m, 2H), 3.78 (s, 1H), 3.83
(s, 3H), 3.92–4.01 (m, 2H), 4.08–4.14 (m, 6H). IR (KBr):
3540, 1720, 1705, 1670, 1620 cm–1. HRMS (FAB) Calcd. for
C23H32N4O8S 524.1941, Found 524.1930.
IIn: Yield 37.7%. 1H NMR (CDCl3): δ 1.25 (d, 3H,
J = 6.2 Hz), 1.36 (d, 3H, J = 6.2 Hz), 1.71 (bs, 2H), 1.97–
2.13 (m, 2H), 3.25–3.27 (m, 1H), 3.29–3.53 (m, 3H), 3.60–
3.79 (m, 3H), 4.04–4.14 (m, 3H), 4.16–4.27 (m, 2H), 4.56
(dd, 3H, J = 5.4 and 14.4 Hz), 4.65–4.73 (m, 1H), 4.80 (dd,
2H, J = 7.8 and 14.6 Hz), 4.86–5.35 (m, 3H), 5.42 and 5.47
(2s, 1H), 5.89–6.00 (m, 2H).
IIIf: Yield 23.5%. UV λmax: 298 nm. m.p.: 128–134 °C
1
(dec.). H NMR (D2O): δ 1.08 (d, 3H, J = 6.2 Hz), 1.17 (d,
3H, J = 4.8 Hz), 1.79–1.90 (m, 1H), 2.58–2.73 (m, 2H),
2.79–2.89 (m, 1H), 3.26–3.35 (m, 2H), 3.52–3.67 (m, 2H),
3.75–3.76 (m, 6H), 3.90–3.93 (m, 1H), 4.04–4.20 (m, 4H).
IR (KBr): 3510, 1730, 1710, 1630 cm–1. HRMS (FAB)
Calcd. for C20H28N4O6S 452.1730, Found 452.1734.
3.7. (1R,5S,6S)-6-[(1R)-hydroxyethyl]-2-[[5-(4-hydroxyimino-
3-ethoxycarbonypyrrolidinyl)car bonyl]pyrrolidin-3-ylthio]-1-
methylcarbapen-2-em-3-carboxylic acid (IIIa)
IIIg: Yield 18.2%. UV λmax: 298 nm. 1H NMR (D2O): 1.09
(d, 3H, J = 6.1 Hz), 1.17 (d, 3H, J = 4.7 Hz), 1.91–1.98 (m,
1H), 2.06–2.12 (m, 1H), 2.63–2.67 (m, 1H), 2.70–2.74 (m,
1H), 2.92–3.00 (m, 1H), 3.34–3.40 (m, 2H), 3.44–3.54 (m,
1H), 3.60–3.70 (m, 1H), 3.75–4.07 (m, 5H), 4.11–4.15 (m,
2H). IR (KBr): 3440, 1710, 1690, 1670, 1630 cm–1. HRMS
(FAB) Calcd. for C19H25N3O6S 423.1464, Found 423.1464.
IIIh: Yield 33.2%. UV λmax: 298 nm. m.p.: 125–130 °C
To a stirred solution of IIa (0.1 g, 0.2 mmol) and Pd(PPh3)4
(30 mg) in CH2Cl2 (10 ml) was added drop-wise n-tributylin
hydride (0.1 ml, 0.25 mmol) at 0 °C and was stirred for 1 h at
same temperature. To the resulting solution was diluted with
water (10 ml) and the organic layers was 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 nm
were collected and lyophilized again to give the title compound
IIIa as an amorphous solid. Yield 27.5%. UV λmax: 298 nm.
1
(dec.). H NMR (D2O): δ 1.08–1.17 (m, 6H), 1.23 (d, 3H,
J = 4.5 Hz), 174–2.00 (m, 2H), 2.11 (s, 1H), 2.38–2.79 (m,
2H), 3.12–3.27 (m, 4H), 3.33–3.43 (m, 2H), 3.60 (s, 2H),
3.84 (S, 1H), 4.10–4.13 (m, 4H), 4.21–4.39 (m, 2H). IR
(KBr): 3490, 1710, 1690, 1670 cm–1. HRMS (FAB) Calcd. for
C23H33N3O8S 511.1988, Found 511.1987.
1
m.p.: 102–110 °C (dec.). H NMR (D2O): δ 1.09–1.19 (m,
9H), 1.90–1.98 (m, 2H), 2.96–3.00 (m, 1H), 3.18–3.30 (m,
1H), 3.36–3.40 (m, 3H), 3.63–3.70 (m, 2H), 3.72–3.84 (m,

H.C. Jeon et al. / European Journal of Medicinal Chemistry 41 (2006) 1201–1209
1209
1
IIIi: Yield 14.0%. UV λmax: 298 nm. H NMR (D2O): δ
1.11 (d, 3H, J = 7.8 Hz), 1.17 (d, 3H, J = 4.7 Hz), 1.30–1.47
(m, 2H), 1.81–1.91 (m, 2H), 2.11 (s, 1H), 3.19–3.27 (m, 3H),
3.35–3.39 (m, 3H), 3.57–3.68 (m, 3H), 3.86–3.95 (m, 3H),
4.12–4.15 (m, 2H). IR (KBr): 3440, 1710, 1670 cm–1. HRMS
(FAB) Calcd. for C20H29N3O6S 439.1777, Found 439.1770.
2H), 3.79–3.82 (m, 4H), 3.92–4.11 (m, 1H), 4.14 (d, 2H,
J = 6.6 Hz). IR (KBr): 3490, 1710, 1690, 1660 cm–1. HRMS
(FAB) Calcd. for C20H27N3O6S 437.1621, Found 437.1630.
References
1
IIIj: Yield 10.5%. UV λmax: 298 nm. H NMR (D2O) δ
[1] W. Leanza, K. Wildonger, T.W. Miller, B.G. Christensen, J. Med. Chem.
22 (1979) 1435–1436.
[2] J. Birnbaum, F.M. Kahan, J.S. MacDonald, Am. J. Med. 78 (Suppl. 6A)
(1985) 3–21.
[3] M. Sunagawa, H. Matsumure, T. Inoue, M. Fukasawa, M. Kato, J. Anti-
biot. 43 (1990) 519–532.
[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) 1996–2001.
[5] D.H. Shih, F.L. Baker, B.G. Christensen, Heterocycles 21 (1984) 29–40.
[6] D.H. Shih, F.L. Baker, B.G. Christensen, Tetrahedron Lett. 26 (1985)
587–590.
[7] M. Sato, M. Takemura, S. Atarashi, K. Higashi, T. Nagahara, M. Furu-
kawa, T. Ikeuchi, Y. Osada, J. Antibiot. 40 (1987) 1292–1302.
[8] Y. Iso, T. Irie, Y. Nishino, K. Motokawa, Y. Nishitani, J. Antibiot. 49
(1996) 199–209.
[9] K. Inoue, Y. Hamana, T. Inoue, M. Fukasawa, M. Kato, Abstracts of
Papers of 34th Intersci. Conf. On Antimicro. Agents Chemother., no 1,
Orlando, 1994.
[10] N. Sato, F. Ohba, Drugs future 21 (1996) 361–365.
[11] C.-H. Oh, J.-H. Cho, J. Antibiot. 47 (1994) 126–128.
[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) 59–67.
[13] 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) 152–158.
[14] C.-H. Oh, H.-G. Dong, H.-W. Cho, S.J. Park, J.H. Hong, J.-H. Cho,
Arch. Pharm. Pharm. Med. Chem. 335 (2002) 200–206.
[15] C.-H. Oh, H.-W. Cho, J.-H. Cho, Eur. J. Med. Chem. 37 (2002) 743–
754.
[16] M. Sunagawa, M. Itho, K. Kubota, A. Sasaki, Y. Ueda, J. Antibiot. 55
(2002) 722–757.
[17] B. Nicolae, B. Constantin, B. Emila, C. Olga, B. Rom, Revistade Chimie
34 (1983) 699–706.
1.10–1.17 (m, 6H), 1.20 (d, 3H J = 6.4 Hz), 1.65–1.72 (m,
1H), 1.82–1.87 (bs, 2H), 2.13 (m, 1H), 2.53 (bs, 1H), 2.83–
3.05 (m, 2H), 3.19–3.49 (m, 3H), 3.53–3.60 (m, 3H), 3.76–
3.81 (m, 3H), 3.92 (bs, 1H), 4.32–4.40 (m, 2H). IR (KBr):
3490, 1720, 1690, 1670, 1610 cm–1. HRMS (FAB) Calcd. for
C23H32N4O8S 524.1941, Found 524.1939.
IIIk: Yield 18.4%. UV λmax: 298 nm. m.p.: 127–131 °C
(dec.). H NMR (D2O): δ 1.10 (d, 3H, J = 7.2 Hz), 1.18 (d,
1
3H, J = 6.3 Hz), 1.81–1.93 (m, 1H), 2.12 (s, 1H), 2.58 (bs,
3H), 2.89–3.11 (m, 2H), 3.36–3.43 (m, 3H), 3.55–3.78 (m,
6H), 4.12–4.19 (m, 2H). IR (KBr): 3460, 1710, 1680,
1590 cm–1. HRMS (FAB) Calcd. for C20H28N4O6S 452.1730,
Found 452.1730.
1
IIll: Yield 13.5%. UV λmax: 298 nm. H NMR (D2O): δ
1.10–1.16 (m, 6H), 1.19 (d, 3H J = 6.9 Hz), 1.65–1.72 (m,
1H), 1.82–1.89 (m, 2H), 2.13 (s, 1H), 2.53 (bs, 1H), 2.67–
3.07 (m, 2H), 3.16–3.47 (m, 6H), 3.53–3.63 (m, 3H), 3.76–
3.81 (m, 3H), 3.92 (s, 1H), 4.02–4.19 (m, 2H). IR (KBr):
3490, 1710, 1695, 1670, 1580 cm–1. HRMS (FAB) Calcd. for
C24H34N4O8S 538.2097, Found 538.2090.
1
IIIm: Yield 19.4%. UV λmax: 298 nm. H NMR (D2O): δ
1.12 (d, 3H, J = 7.2 Hz), 1.19 (d, 3H, J = 6.3 Hz), 1.81–1.90
(m, 2H), 2.91–2.96 (m, 2H), 2.57–2.65 (m, 2H), 3.25–3.38 (m,
3H), 3.54–3.68 (m, 6H), 3.75 (s, 3H), 3.79–4.10 (m, 1H),
4.12–4.15 (m, 2H). IR (KBr): 3490, 1710, 1670, 1570 cm–1.
HRMS (FAB) Calcd. for C21H30N4O6S 466.1886, Found
466.1897.
IIIn: Yield 10%. UV λmax: 298 nm. m.p.: 129–134 °C
(dec.). H NMR (D2O): δ 1.12 (d, 3H, J = 7.2 Hz), 1.20 (d,
[18] M. Solymar, E. Forro, F. Fulop, Tetrahedron Asymmetry 15 (2004)
3281–3287.
1
3H, J = 6.6 Hz), 1.75–1.82 (m, 2H), 2.51–2.56 (m, 4H),
2.92–3.00 (m, 1H), 3.38 (d, 2H, J = 3.6 Hz), 3.45–3.72 (m,
[19] N.S. Shaikh, V.H. Deshpande, A.V. Bedekar, Tetrahedron 57 (2001)
9045–9048.