Synthesis and biological activity of 1β-methyl-2-[5-(2-N-substituted aminoethylcarbamoyl)pyrrolidin-3-ylthio]carbapenem derivatives

Article abstract of DOI:10.1016/S0223-5234(03)00143-0

The synthesis of a new series of 1β-methylcarbapenems having the substituted aminoethylcarbamoylpyrrolidine moiety is described. Their in vitro antibacterial activities against both Gram-positive including MRSA and Gram-negative bacteria were tested and the effect of substituent on the pyrrolidine ring was investigated. In particular, the compound 11g having piperazinyl urea moiety showed the most potent antibacterial activity and 11k exhibited excellent anti-MRSA.

Full text of DOI:10.1016/S0223-5234(03)00143-0

European Journal of Medicinal Chemistry 38 (2003) 841ꢀ850
/
www.elsevier.com/locate/ejmech
Short communication
Synthesis and biological activity of 1b-methyl-2-[5-(2-N-substituted
aminoethylcarbamoyl)pyrrolidin-3-ylthio]carbapenem derivatives
Chang-Hyun Oh a, Su-Chul Lee b, Jung-Hyuck Cho a,*
a Medicinal Chemistry Research Center, Korea Institute of Science and Technology, Seoul 130-650, South Korea
b Hawon Pharm. Co., Seoul 135-080, South Korea
Received 27 February 2003; received in revised form 23 June 2003; accepted 23 June 2003
Abstract
The synthesis of a new series of 1b-methylcarbapenems having the substituted aminoethylcarbamoylpyrrolidine moiety is
described. Their in vitro antibacterial activities against both Gram-positive including MRSA and Gram-negative bacteria were
tested and the effect of substituent on the pyrrolidine ring was investigated. In particular, the compound 11g having piperazinyl urea
moiety showed the most potent antibacterial activity and 11k exhibited excellent anti-MRSA.
´
# 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: 1b-Methylcarbapenem; Antibacterial activity; Substituent effect
1. Introduction
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.
A number of carbapenem antibiotics, for example
imipenem, panipenem and meropenem, are currently in
clinical use due to their broad antibacterial spectra and
potent bactericidal effects [1]. However, a number of
problems still remain with these agents, in particular,
activity against resistant Gram-positive bacteria such as
methicillin-resistant Staphylococcus aureus (MRSA) and
the Gram-negative pathogen Pseudomonas aeruginosa,
is relatively weak. During the past decade, extensive
synthetic efforts have been made to confer anti-MRSA
activity on b-lactams such as a cephalosporin [2] or a
carbapenem [3]. As a result, some cephalosporin and
carbapenem derivatives with potent in vitro anti-MRSA
activity were identified by 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.
Previously, we reported that the carbapenem com-
pounds which have a pyrrolidine-3-ylthio group at the
C-2 position in the carbapenem skeleton are noted for
their broad and potent antibacterial activity, and a large
number of derivatives have been synthesised and
investigated [7ꢀ
In this paper, we described the synthesis and
structureꢀactivity relationships of the 1b-methylcarba-
/
13].
/
penems having a 5?-substituted aminoethylcarbamoyl
pyrrolidine-3?-ylthio group as a C-2 side chain and our
approach for improvement of anti-MRSA and antibac-
terial activity of the carbapenems is discussed.
2. Results and discussion
2.1. Chemistry
From the literature of carbapenem antibiotics, espe-
cially the SAR related to meropenem [4,5] and panipe-
nem [6], the importance of a pyrrolidine ring for potent
activity and high PBP affinity were noted. Thus we
Our general synthetic route leading to new carbape-
nems involved the preparation of appropriately pro-
tected thiols containing pyrrolidine ring as a side chain
and subsequent coupling reaction with the carbapenem
diphenylphosphates, followed by deprotection of the
resulting protected carbapenems in a usual manner. 2-
* Correspondence and reprints.
E-mail address: choh@kist.re.kr (J.-H. Cho).
´
0223-5234/03/$ - see front matter # 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
doi:10.1016/S0223-5234(03)00143-0

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C.-H. Oh et al. / European Journal of Medicinal Chemistry 38 (2003) 841ꢀ850
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Scheme 1. (i) 4 N NaOHꢀMeOH; (ii) (1) ethyl chloroformate, TEA, CH2Cl2, (2) ethanolamine, EtOH; (iii) MsCl, TEA, CH2Cl2; (iv) NaN3, DMSO;
/
(v) PPh3, H2O, THF; (vi) corresponding chloride, TEA, CH2Cl2; (vii) (1) p-Nitrophenyl chloroformate, TEA, CH2Cl2, (2) R2NH, EtOH; (viii)
trifluoroacetic acid, triethyl silane, CH2Cl2.
(N-substituted aminoethylcarbamoyl)-Pyrrolidine deri-
vatives (8aꢀm) were prepared by the sequence shown in
Schemes 1ꢀ4. N-Protected proline methyl ester [13] was
tives (7iꢀ
formidiate, ethyl acetimidate and 1H-pyrazole-1-car-
boxamidine hydrochloride (Scheme 3). Compounds 7lꢀ
/
k) were prepared by reaction of 6 with ethyl
/
/
/
converted to the carboxylic acid 2 by treatment of 4 N
NaOH and subsequently treated with ethyl chlorofor-
mate and ethanolamine to provide 3. Compound 3 was
reacted with mesylchloride and subsequently treatment
with sodium azide in DMSO gave the azide compound
5, which was successfully converted into amine 6 using
triphenylphosphine. Treatment of 6 with allyl chloro-
formate, mesyl chloride and dimethylsulfamoyl chloride
afforded the corresponding N-acylated products, 7a, 7b
and 7c. Carbamoylation of amine was carried out by a
conventional method using p-nitrophenyl chlorofor-
m were obtained by reaction of mesylate 4 with
thiomorpholine and piperazine (Scheme 4). Deprotec-
tion of the trityl group to mercaptans (8aꢀ
achieved by treatment of 7aꢀm with trifluoroacetic acid
in the presence of triethylsilane.
Finally, the reaction of 9 [9] with thiols (8aꢀ
presence of diisopropylethylamine provided the corre-
sponding 2-substituted carbapenems (10aꢀm), respec-
/m) were
/
/m) in the
/
tively. Derivatives 10l and 10m containing cyclic amine
substituents were converted to quaternary salts by
methyl iodide and deprotected to give 11lQ and
11mQ. Deprotection of these compounds by catalytic
hydrogenation gave the crude products, which were
purified by HP-20 column to give the pure carbapenems
mate to give urea type compounds 7dꢀg (Scheme 1).
/
Preparation of the thiourea type compound (7h) was
accomplished by treatment of compound 6 with methy-
lisothiocyanate reagent (Scheme 2). The imine deriva-
(11aꢀmQ) (Scheme 5).
/
Scheme 2. (i) Methyl isothiocyanate, TEA, CH2Cl2; (ii) trifluoroacetic acid, triethyl silane, CH2Cl2.

C.-H. Oh et al. / European Journal of Medicinal Chemistry 38 (2003) 841ꢀ
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850
843
Scheme 3. (i) Ethyl acetimidate×
/
HCl, EtOH; (ii) ethyl formidiate×
/
HCl, EtOH; (iii) 1H-pyrazole-1-carboxamidine×/HCl, EtOH; (iv) trifluoroacetic
acid, triethyl silane, CH2Cl2; (v) allyl chloroformate, TEA, CH2Cl2.
2.2. Biological assay
hydrolysing 1 mM of glycyldehydrophenylalanine per
min when the substrate, 50 mM, was incubated at 35 8C
in 50 mM MOPS buffer, pH 7.0.
2.2.1. 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 per mL
with the same broth and inoculated with an inoculating
device onto agar containing serial twofold dilutions of
the test compounds. Organisms were incubated at 37 8C
2.2.3. Antibacterial activity studies
The in vitro antibacterial activities of the new
carbapenems (11aꢀmQ) prepared above against Gram-
/
positive and negative bacteria including strains of
MRSA are listed in Tables 1 and 2. For comparison,
the MIC values of imipenem, meropenem and vanco-
mycin are also listed. Among these compounds, 11c,
11g, 11k and 11i showed superior or similar antibacter-
ial activity against Gram-positive bacteria to Merope-
nem, and exhibited improved antibacterial activity
against Gram-negative bacteria than Imipenem.
As to the substituent of the aminoethylcarbamoyl side
chain, the compounds 11f and 11g having cyclic urea
moieties were generally more potent than the non urea
compounds 11l and 11m. Comparing the compounds
for 18ꢀ20 h. The MICs of a compound were defined as
/
the lowest concentration that visibly inhibited growth.
2.2.2. Determination of susceptibility to renal
dehydropeptidase-I (DHP-I)
The relative hydrolysis rate of carbapenems by
porcine renal DHP-I was determined, taking the initial
hydrolysis rate of imipenem as 1.0. Partially purified
porcine DHP-I (final concentration, 0.3 U mLꢁ1) was
incubated with 50 mM carbapenem at 35 8C in 50 mM
MOPS buffer, pH 7.0. The initial hydrolysis rate was
monitored by the spectrophotometric method. One unit
of activity was defined as the amount of enzyme
11eꢀg having cyclic urea moieties showed slight differ-
/
ences in the antibacterial activities against Gram-posi-
tive and negative bacteria. As expected, the piperazine
Scheme 4. (i) Thiomorpholine or piperazine, CH3CN; (ii) trifluoroacetic acid, triethyl silane, CH2Cl2.

844
C.-H. Oh et al. / European Journal of Medicinal Chemistry 38 (2003) 841ꢀ850
/
Scheme 5. (i) Diisopropylethyl amine, 8aꢀ
/
m, CH3CN; (ii) methyl iodide, acetone; (iii) Pd(OH)2ÃC, H2.
/
urea compound 11g exhibited the most potent and well-
balanced activity. Furthermore, we observed that the
thiomorpholine urea 11f is more potent than the
morpholine urea 11e. Introduction of sulphamoyl group
(11c) led to significantly enhanced antibacterial activity
against Gram-negative bacteria compared with carba-
moyl group (11d). The quaternised compounds (11lQ,
11mQ) showed more improved activity against P.
aeruginosa than the unquaternised compounds (11l,
11m).
The anti-MRSA activity was the best when the
substituent is guanidine moiety (11k), whereas it pos-
sessed low activity against Gram-negative bacteria.
The stability to DHP-I of most compounds was tested
and all the compounds were more stable than Merope-
nem. In particular, the quaternised compounds 11lQ
and 11mQ exhibited the most stability.
standard. The HRMS spectra were obtained with JEOL
Model JMS-700 High Resolution Mass Spectrometer.
3.1. (2S,4S)-4-tritylthio-1-
(allyloxycarbonyl)Pyrrolidine-2-carboxylic acid (2)
To a solution of 1 (48.7 g, 0.10 mol) in MeOH (500
mL) was added slowly 4 N NaOH (38 mL, 0.15 mol) at
0 8C and was stirred for 5 h at room temperature (r.t.).
The mixture was neutralised with 4 N HCl (38 mL) and
concentrated, and the resulting residue was diluted with
water (300 mL) and ethyl acetate (200 mL). The
resulting precipitates were filtered and the solid was
washed with water, and dried in air to give 2 (39.4 g,
1
83.2%) as a white solid. M.p. 202ꢀ
NMR (CDCl3) d 1.98 (m, 1H), 2.75ꢀ
(m, 1H), 3.55 (bs, 2H), 3.98 (m, 1H), 4.55 (d, 2H, Jꢂ
/
203 8C (dec.). H-
/
2.82 (m, 1H), 3.01
/5.9
Hz), 5.25 (m, 2H), 5.90 (m, 1H), 7.27 (m, 9H), 7.47 (m,
6H), 12.7 (bs, 1H). 13C-NMR (CDCl3): 36.7, 41.2, 53.3,
58.8, 65.7, 67.6, 118.2, 127.3, 128.5, 129.9, 132.7, 144.9,
153.8, 174.4. IR (KBr): 3440, 3060, 1745, 1670 cmꢁ1
.
3. Experimental part
Melting point (m.p.): Thomas Hoover apparatus,
uncorrected. UV spectra: Hewlett-Packard 8451A
3.2. (2S,4S)-2-(2-hydroxyethylcarbamoyl)-4-tritylthio-
1-(allyloxycarbonyl)Pyrrolidine (3)
UVꢀ
/
vis spectrophotometer. IR spectra: PerkinꢀElmer
/
16F-PC FTIR. NMR spectra: Varian Gemini 300
spectrometer, tetramethylsilane (TMS), as an internal
A solution of 2 (23.7 g, 0.05 mol) and triethylamine
(7.4 mL, 0.055 mol) in dry CH2Cl2 (300 mL) was cooled

C.-H. Oh et al. / European Journal of Medicinal Chemistry 38 (2003) 841ꢀ
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850
845
Table 2
Anti-MRSA activities of 11g, 11i and 11k
Methicillin resistant strains
11g
11i
11k
Vancomycin
S. aureus LG001
S. aureus LG002
S. aureus Y8012954
S. aureus QRS179
S. aureus QRS241
S. aureus Hoechst208E
S. aureus KIST2
S. aureus KIST5
1.563 1.563 0.391 1.563
0.391 0.195 0.098 0.781
0.195 0.195 0.049 0.781
0.391 0.391 0.195 0.781
0.391 0.391 0.195 0.781
0.195 0.195 0.098 0.781
6.25
6.25
1.56
0.781
0.781 0.781 0.195 0.781
to 0 8C under nitrogen and treated with ethyl chlor-
oformate (5.25 mL, 0.055 mol). The mixture was stirred
at 0 8C for 30 min, added with ethanolamine (3.3 mL,
0.055 mol) and stirred at 0 8C for 1 h. The mixture was
washed with 10% NaHCO3 and brine, and was 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 (23.1 g, 89.5%) as
1
a pale yellow oil. Rf 0.3 (ethyl acetate:n-Hex, 2:1). H-
NMR (CDCl3) d 1.95 (bs, 1H), 2.20 (bs, 1H), 2.75ꢀ
(bs, 1H), 2.96 (bs, 1H), 3.55 (t, 2H, Jꢂ5.6 Hz), 4.01 (m,
4.62 (bs, 3H), 5.28
/2.86
/
1H), 4.11 (t, 2H, Jꢂ
/
5.6 Hz), 4.50ꢀ
/
(m, 2H), 5.87 (m, 1H), 7.27 (m, 9H), 7.48 (m, 6H). 13C-
NMR (CDCl3): 36.7, 41.9, 42.7, 53.3, 60.6, 61.8, 66.7,
67.9, 118.2, 127.3, 128.5, 129.9, 132.7, 144.9, 156.8,
172.4. IR (KBr): 3330, 2940, 1710, 1670 cmꢁ1
.
3.3. (2S,4S)-2-(2-mesyloxyethylcarbamoyl)-4-
tritylthio-1-(allyloxycarbonyl)Pyrrolidine (4)
A solution of 3 (20.6 g, 0.04 mol) and triethylamine
(5.9 mL, 0.044 mol) in dry CH2Cl2 (200 mL) was cooled
to 0 8C under nitrogen and treated with methanesulfonyl
chloride (5.01 g, 0.044 mol). The mixture was stirred at
0 8C for 1 h, diluted with CH2Cl2 (200 mL), and washed
with 10% NaHCO3 and brine. The organic layer was
dried over anhydrous Na2SO4. Evaporation of the
solvent in vacuo gave a crude residue, which was
purified by silica gel column chromatography to give 4
(21.8 g, 91.7%) as a pale yellow oil. Rf 0.4 (ethyl
acetate:n-Hex, 2:1). 1H-NMR (CDCl3) d 1.99 (bs,
1H), 2.21 (bs, 1H), 2.75ꢀ
4H), 3.55 (t, 2H, Jꢂ5.6 Hz), 4.01 (m, 1H), 4.25 (t, 2H,
Jꢂ5.6 Hz), 4.50ꢀ4.59 (bs, 3H), 5.28 (m, 2H), 5.88 (m,
/
2.82 (bs, 1H), 2.96ꢀ
/
3.08 (bs,
/
/
/
1H), 7.27 (m, 9H), 7.48 (m, 6H). 13C-NMR (CDCl3):
30.7, 36.7, 39.7, 41.9, 52.5, 60.8, 61.6, 66.8, 67.8, 118.0,
127.3, 128.5, 129.9, 132.7, 144.9, 156.0, 171.8. IR (KBr):
3430, 2920, 1740, 1700, 1440 cmꢁ1
.
3.4. (2S,4S)-2-(2-azidoethylcarbamoyl)-4-tritylthio-1-
(allyloxycarbonyl)Pyrrolidine (5)
A mixture of 4 (31.5 g, 0.053 mol) and sodium azide
(13.8 g, 0.21 mol) in DMSO (300 mL) was heated at

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C.-H. Oh et al. / European Journal of Medicinal Chemistry 38 (2003) 841ꢀ850
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70 8C for 5 h. The reaction mixture was poured into ice
water and extracted with ethyl acetate (300 mLꢃ2).
The organic layer was successively washed with water
(200 mLꢃ2), brine and dried over anhydrous Na2SO4.
Compounds 7b and 7c were also prepared as de-
scribed for the preparation of 7a using the correspond-
ing sulfonyl chlorides.
/
/
Evaporation of the solvent in vacuo gave a crude
residue, which was purified by silica gel column
chromatography to give 5 (24.5 g, 85.4%) as a pale
3.6.1. Compound 7b
Yield 82.5%. Rf 0.6 (ethyl acetate). 1H-NMR (CDCl3)
d 1.91 (bs, 1H), 2.13 (m, 1H), 2.83ꢀ
/
3.12 (bs, 6H), 3.25ꢀ
/
1
yellow oil. Rf 0.6 (ethyl acetate:n-Hex, 1:1). H-NMR
3.48 (bs, 4H), 3.93 (m, 1H), 4.55 (bs, 2H), 5.25 (m, 2H),
5.88 (m, 1H), 6.44 (bs, 1H), 7.23 (m, 9H), 7.47 (m, 6H).
(CDCl3) d 2.13 (m, 1H), 2.82 (m, 1H), 2.95ꢀ
/3.08 (m,
1H), 3.39ꢀ3.48 (m, 5H), 4.05 (bs, 1H), 4.14 (m, 1H), 4.55
/
(m, 2H), 5.29 (m, 2H), 5.88 (m, 1H), 7.27 (m, 9H), 7.46
(m, 6H). 13C-NMR (CDCl3): 35.7, 39.3, 41.9, 51.1, 53.5,
60.4, 66.8, 67.9, 118.2, 127.3, 128.5, 129.9, 132.7, 144.9,
3.6.2. Compound 7c
Yield 81.8%. Rf 0.7 (ethyl acetate). 1H-NMR (CDCl3)
d 1.94 (bs, 1H), 2.22 (m, 1H), 2.78 (s, 6H), 2.90ꢀ
/3.22
155.6, 171.7. IR (KBr): 3320, 2100, 1720, 1670 cmꢁ1
.
(bs, 2H), 3.20ꢀ3.32 (bs, 3H), 3.36ꢀ3.51 (bs, 2H), 3.93
/
/
(m, 1H), 4.55 (bs, 2H), 5.25 (m, 2H), 5.88 (m, 1H), 6.74
(bs, 1H), 7.23 (m, 9H), 7.47 (m, 6H).
3.5. (2S,4S)-2-(2-aminoethylcarbamoyl)-4-tritylthio-1-
(allyloxycarbonyl)Pyrrolidine (6)
3.7. (2S,4S)-2-[2-(3,3-
dimethylureido)ethylcarbamoyl]-4-tritylthio-1-
(allyloxycarbonyl)Pyrrolidine (7d)
A mixture of 5 (1.29 g, 2.4 mmol), triphenylphosphine
(0.70 g, 2.6 mmol) and H2O (0.44 mL, 24.0 mmol) in
THF (10 mL) was heated at 40 8C for 4 h. After cooling,
the reaction mixture was diluted with H2O (20 mL) and
ethyl acetate (30 mL). The organic layer was successively
washed with water, brine 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 6 (1.07 g, 86.4%) as a pale
To a solution of 6 (1.03 g, 2.0 mmol) and triethyla-
mine (0.30 mL, 2.2 mmol) in dry CH2Cl2 (30 mL) was
added slowly p-nitrophenyl chloroformate (0.44 g, 2.2
mmol) at 0 8C and was stirred for 1 h at same
temperature. The mixture was diluted with H2O (30
mL), CH2Cl2 (50 mL) and washed with brine. The
organic layer was concentrated in vacuo to give a
residue, which was used without further purification.
To the solution of residue in ethanol (20 mL) was added
N,N-dimethylamine (2 mL) and stirred for 1 h at r.t.
The reaction mixture was neutralised with 6 N HCl,
diluted with ethyl acetate (100 mL), and washed with
brine. The organic layer was dried over anhydrous
Na2SO4, which was purified by silica gel column
chromatography to give 7d (0.99 g, 81.6%) as a pale
1
yellow oil. Rf 0.2 (ethyl acetate:MeOH, 2:1). H-NMR
(CDCl3) d 1.88 (m, 1H), 2.19 (m, 1H), 2.82ꢀ
/2.94 (bs,
2H), 2.95ꢀ3.08 (bs, 1H), 3.30ꢀ3.48 (bs, 4H), 4.02 (bs,
/
/
1H), 4.55 (bs, 2H), 5.22 (m, 2H), 5.84 (m, 1H), 7.27 (m,
9H), 7.46 (m, 6H). 13C-NMR (CDCl3): 37.2, 40.6, 41.7,
53.2, 53.8, 60.1, 66.6, 67.7, 117.7, 127.3, 128.5, 129.9,
132.7, 144.9, 155.7, 172.9. IR (KBr): 3430, 3060, 1720,
1670 cmꢁ1
.
1
yellow oil. Rf 0.8 (ethyl acetate). H-NMR (CDCl3) d
1.92 (bs, 1H), 2.19 (m, 1H), 2.83ꢀ/2.89 (bs, 1H), 2.96 (2s,
3.6. (2S,4S)-2-(2-
allyloxycarbonylaminoethylcarbamoyl)-4-tritylthio-1-
(allyloxycarbonyl)Pyrrolidine (7a)
6H), 3.04 (bs, 1H), 3.29ꢀ3.56 (bs, 5H), 4.01 (m, 1H),
4.55 (bs, 2H), 5.26 (bs, 2H), 5.85 (m, 1H), 6.86 (bs, 1H),
7.24 (m, 9H), 7.45 (m, 6H).
/
The compounds 7eꢀg were also prepared as described
/
To a solution of 6 (1.3 g, 2.5 mmol) and triethylamine
(0.37 mL, 2.75 mmol) in dry CH2Cl2 (20 mL) was added
slowly allyl chloroformate (0.34 g, 2.75 mmol) at 0 8C
and was stirred for 1 h at same temperature. The
mixture was diluted with H2O (100 mL), CH2Cl2 (100
mL) and washed with brine. The organic layer was dried
over anhydrous Na2SO4, concentrated, and the resulting
residue was purified by silica gel column chromatogra-
phy to give 7a (1.30 g, 87.1%) as a pale yellow oil. Rf 0.7
(ethyl acetate:n-Hex, 2:1). 1H-NMR (CDCl3) d 1.85 (bs,
for the preparation of 7d using the corresponding
amines.
3.7.1. Compound 7e
Yield 76.2%. Rf 0.3 (ethyl acetate). 1H-NMR (CDCl3)
d 1.90 (bs, 1H), 2.22 (m, 1H), 2.73ꢀ
/
2.80 (m, 1H), 2.93ꢀ
/
3.03 (bs, 2H), 3.21ꢀ3.52 (bs, 8H), 3.65 (bs, 4H), 3.96 (m,
/
1H), 4.49 (bs, 2H), 5.26 (m, 2H), 5.88 (m, 1H), 6.84 (bs,
1H), 7.27 (m, 9H), 7.47 (m, 6H).
1H), 2.22 (m, 1H), 2.63ꢀ
5H), 3.59 (bs, 1H), 4.04 (m, 1H), 4.50ꢀ
5.20ꢀ5.44 (m, 4H), 5.80ꢀ5.98 (m, 2H), 6.24 (bs, 1H),
7.23 (m, 9H), 7.47 (m, 6H).
/
2.80 (bs, 1H), 3.28ꢀ
/
3.55 (bs,
3.7.2. Compound 7f
Yield 75.1%. Rf 0.2 (ethyl acetate). 1H-NMR (CDCl3)
/4.62 (bs, 4H),
/
/
d 1.92 (bs, 1H), 2.20 (m, 1H), 2.52 (bs, 4H), 2.73ꢀ
/2.82
(m, 1H), 2.95ꢀ3.05 (bs, 2H), 3.29ꢀ3.50 (bs, 4H), 3.62
/
/

C.-H. Oh et al. / European Journal of Medicinal Chemistry 38 (2003) 841ꢀ
/
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847
(bs, 4H), 3.95 (m, 1H), 4.49 (bs, 2H), 5.26 (m, 2H), 5.67
(bs, 1H), 5.88 (m, 1H), 6.80 (bs, 1H), 7.27 (m, 9H), 7.47
(m, 6H).
3.9.1. Compound 7j
Yield 70.2%. Rf 0.5 (ethyl acetate:n-Hex, 2:1). 1H-
NMR (CDCl3) d 1.85 (bs, 1H), 2.19 (m, 1H), 2.24 (s,
3H), 2.80ꢀ
(bs, 4H), 3.96 (m, 1H), 4.45 (bs, 2H), 4.70 (d, 2H, Jꢂ
Hz), 5.20ꢀ5.44 (m, 4H), 5.85ꢀ6.04 (m, 2H), 6.66 (bs,
1H), 7.23 (m, 9H), 7.47 (m, 6H).
/
2.92 (bs, 1H), 3.02ꢀ
/
3.17 (bs, 2H), 3.30ꢀ
/
3.56
3.7.3. Compound 7g
Yield 74.9%. Rf 0.5 (ethyl acetate). 1H-NMR (CDCl3)
/5.9
/
/
d 1.92 (bs, 1H), 2.23 (m, 1H), 2.73ꢀ
/
2.82 (bs, 1H), 2.93ꢀ
/
3.05 (bs, 2H), 3.21ꢀ3.65 (bs, 12H), 3.96 (m, 1H), 4.49
(bs, 2H), 5.26 (m, 2H), 5.70 (bs, 1H), 5.84 (m, 1H), 6.77
(bs, 1H), 7.27 (m, 9H), 7.47 (m, 6H).
/
Compound 7k was also prepared as described for the
preparation of 7i using the 1H-pyrazole-1-carboxami-
dine hydrochloride.
3.8. (2S,4S)-2-[2-(3-
methylthioureido)ethylcarbamoyl]-4-tritylthio-1-
(allyloxycarbonyl)Pyrrolidine (7h)
3.9.2. Compound 7k
Yield 75.1%. Rf 0.7 (ethyl acetate:n-Hex, 2:1). 1H-
NMR (CDCl3) d 1.89 (bs, 1H), 2.19 (m, 1H), 2.80ꢀ
(bs, 1H), 2.95ꢀ3.07 (bs, 2H), 3.30ꢀ3.59 (bs, 4H), 3.96
(m, 1H), 4.25ꢀ4.58 (bs, 4H), 4.72 (d, 2H, Jꢂ5.9 Hz),
5.20ꢀ5.57 (m, 6H), 5.75ꢀ5.98 (m, 3H), 7.23 (m, 9H),
/2.92
/
/
A mixture of 6 (0.80 g, 1.60 mmol), triethylamine
(0.43 mL, 3.20 mmol), methyl isothiocyanate (0.23 mL,
3.20 mmol) in CH2Cl2 (20 mL) was stirred at r.t. for 5 h.
The reaction mixture was diluted with H2O (20 mL) and
CH2Cl2 (30 mL). 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 7h (0.81 g, 88.1%) as a pale
/
/
/
/
7.47 (m, 6H), 8.92 (bs, 1H), 8.96 (bs, 1H).
3.10. (2S,4S)-2-[2-(thiomorpholin-4-
yl)ethylcarbamoyl]-4-tritylthio-1-
(allyloxycarbonyl)Pyrrolidine (7l)
A mixture of 4 (1.2 g, 2.0 mmol) and thiomorpholine
(0.41 g, 4.0 mmol) in CH3CN (20 mL) was stirred at r.t.
for 20 h. The mixture was diluted with 1 N HCl (30 mL),
ethyl acetate (50 mL) and washed with brine. Evapora-
tion of the solvent in vacuo gave a crude residue, which
was purified by silica gel column chromatography to
give 7l (1.03 g, 85.9%) as a pale yellow oil. Rf 0.2 (ethyl
1
yellow oil. Rf 0.6 (ethyl acetate). H-NMR (CDCl3) d
1.92 (bs, 1H), 2.15 (m, 1H), 2.71ꢀ
/
3.06 (5H), 3.16ꢀ3.30
/
(bs, 3H), 3.74 (bs, 2H), 3.97 (m, 1H), 4.42 (m, 1H), 5.26
(m, 2H), 5.98 (m, 1H), 6.79 (bs, 1H), 7.23 (m, 9H), 7.48
(m, 6H).
1
3.9. (2S,4S)-2-[(2-
allyloxycarbonylformimidoyl)aminoethylcarbamoyl]-4-
tritylthio-1-(allyloxy-carbonyl)Pyrrolidine (7i)
acetate). H-NMR (CDCl3) d 1.88 (m, 1H), 2.19 (m,
1H), 2.52 (bs, 1H), 2.55ꢀ/2.98 (bs, 7H), 3.08 (bs, 2H),
3.25ꢀ3.44 (bs, 4H), 3.95 (m, 1H), 4.15 (m, 1H), 4.45 (m,
/
2H), 5.29 (m, 2H), 5.88 (m, 1H), 6.74 (bs, 1H), 7.27 (m,
9H), 7.47 (m, 6H).
Compound 7m was also prepared as described for the
preparation of 7l using the piperazine.
To a solution of 6 (1.03 g, 2.0 mmol) in EtOH was
added dropwise ethyl formidiate hydrochloride (0.24 g,
2.2 mmol) and was heated at reflux for 3 h. Evaporation
of the solvent in vacuo gave a crude residue, which was
used without further purification. To the above solution
and triethylamine (0.30 mL, 2.2 mmol) in dry CH2Cl2
(20 mL) was added slowly allyl chloroformate (0.27 g,
2.2 mmol) at 0 8C and was stirred for 1 h at same
temperature. The mixture was diluted with CH2Cl2 (100
mL) and washed with 10% NaHCO3, brine. The organic
layer was dried over anhydrous Na2SO4, concentrated,
and the resulting residue was purified by silica gel
column chromatography to give 7i (1.00 g, 79.8%) as a
3.10.1. Compound 7m
Yield 72.4%. Rf 0.2 (ethyl acetate). 1H-NMR (CDCl3)
d 1.87 (bs, 1H), 2.18 (m, 1H), 2.37ꢀ
/
2.55 (bs, 6H), 2.77ꢀ
/
2.89 (bs, 1H), 2.94ꢀ3.01 (bs, 2H), 3.22 (bs, 2H), 3.55 (bs,
/
4H), 4.01 (bs, 1H), 4.43 (bs, 2H), 5.04, 5.26 (m, 2H), 5.85
(m, 1H), 6.68 (bs, 1H), 7.24 (m, 9H), 7.45 (m, 6H).
3.11. Allyl(1R,5S,6S)-6-[(1R)-hydroxyethyl]-2-[5-
(2-allyloxycarbonylaminoethylcarbamoyl)]-1-
(allyloxycarbonyl)pyrrolidin-3-ylthio]-1-
1
pale yellow oil. Rf 0.7 (ethyl acetate:n-Hex, 2:1). H-
NMR (CDCl3) d 1.82 (bs, 1H), 2.19 (m, 1H), 2.80ꢀ
(bs, 1H), 3.02ꢀ3.17 (bs, 1H), 3.33ꢀ3.56 (bs, 3H), 3.78
(bs, 2H), 3.96 (m, 1H), 4.55 (bs, 2H), 4.72 (d, 2H, Jꢂ5.9
Hz), 5.20ꢀ5.44 (m, 4H), 5.85ꢀ5.98 (m, 2H), 7.23 (m,
9H), 7.47 (m, 6H), 8.92 (s, 1H).
Compound 7j was also prepared as described for the
preparation of 7i using the ethyl acetimidate hydrochlo-
ride.
/
2.92
methylcarbapen-2-em-3-carboxylate (10a)
/
/
/
To a solution of 7a (0.60 g, 1.0 mmol) in CH2Cl2 (2
mL) was added dropwise triethylsilane (0.13 g, 1.1
mmol) at 5 8C, and then TFA (2 mL). After stirring
for 30 min at r.t., the mixture was evaporated under
reduced pressure. The residue was dissolved with ethyl
acetate and washed with 10% NaHCO3, brine. The
/
/

848
C.-H. Oh et al. / European Journal of Medicinal Chemistry 38 (2003) 841ꢀ850
/
organic layer was concentrated in vacuo to give a
residue (8a), which was used without further purifica-
tion. A solution of allyl (1R,5S,6S)-2-(diphenylpho-
sphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-
2-em-3-carboxylate (9, 0.50 g, 1.0 mmol) in CH3CN (10
mL) was cooled to 0 8C under N2. To this solution was
added diisopropylethylamine (0.13 g, 1.0 mmol) and a
solution of the mercapto compound 8a in CH3CN (5
mL). After stirring for 2 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 chromato-
graphy to give 10a (0.45 g, 71.1%) as a yellow
amorphous solid. Rf 0.3 (ethyl acetate:acetone, 4:1).
3.11.5. Compound 10f
Yield 65.9%. 1H-NMR(CDCl3) d 1.26 (d, 3H, Jꢂ
Hz), 1.38 (d, 3H, Jꢂ6.0 Hz), 2.46 (m, 1H), 2.51 (bs,
4H), 2.79ꢀ2.85 (m, 1H), 3.03ꢀ3.16 (bs, 4H), 3.28ꢀ3.44
(bs, 3H), 3.54ꢀ3.65 (bs, 4H), 3.69 (m, 1H), 3.85 (bs, 1H),
3.99 (bs, 1H), 4.16 (bs, 1H), 4.45 (m, 1H), 4.45ꢀ4.67 (bs,
4H), 5.29ꢀ5.53 (m, 4H), 5.75ꢀ6.01 (bs, 2H).
/7.0
/
/
/
/
/
/
/
/
3.11.6. Compound 10g
Yield 68.4%. 1H-NMR(CDCl3) d 1.26 (d, 3H, Jꢂ
Hz), 1.35 (d, 3H, Jꢂ6.2 Hz), 1.97 (m, 1H), 2.34 (m,
1H), 2.70 (m, 1H), 3.10 (bs, 1H), 3.15ꢀ
3.30ꢀ
2H), 4.19 (m, 1H), 4.29 (m, 1H), 4.45ꢀ
5.26ꢀ5.55 (m, 6H), 5.75ꢀ6.01 (bs, 3H).
/6.7
/
/3.26 (bs, 5H),
/3.49 (bs, 6H), 3.59 (bs, 2H), 3.94 (m, 1H), 4.12 (bs,
/
4.69 (bs, 6H),
1H-NMR (CDCl3) d 1.25 (d, 3H, Jꢂ
3H, Jꢂ6.4 Hz), 2.21 (bs, 1H), 2.46 (bs, 1H), 2.95 (dd,
1H, Jꢂ3.3 and 3.3 Hz), 3.06ꢀ3.55 (bs, 7H), 3.90 (bs,
2H), 4.15 (bs, 1H), 4.19 (bs, 1H), 4.45ꢀ4.69 (bs, 6H),
5.26ꢀ5.55 (m, 6H), 5.75ꢀ6.01 (bs, 3H).
The synthesis of compounds 10bꢀm were carried out
/
7.1 Hz), 1.36 (d,
/
/
/
/
/
3.11.7. Compound 10h
Yield 65.5%. 1H-NMR(CDCl3) d 1.26 (d, 3H, Jꢂ
Hz), 1.35 (d, 3H, Jꢂ6.3 Hz), 1.99 (m, 1H), 2.45 (m,
1H), 2.89 (bs, 3H), 3.11ꢀ3.39 (bs, 4H), 3.44ꢀ3.69 (bs,
3H), 3.80 (m, 1H), 3.91 (m, 1H), 4.06 (m, 1H), 4.16 (m,
1H), 4.33 (m, 1H), 4.47ꢀ4.69 (bs, 4H), 5.26ꢀ5.55 (m,
4H), 5.71ꢀ5.98 (bs, 2H).
/
/6.9
/
/
/
/
/
/
by the same procedure as described for the preparation
of 10a.
/
/
/
3.11.1. Compound 10b
Yield 63.9%. 1H-NMR(CDCl3) d 1.26 (d, 3H, Jꢂ
/
7.1
6.2 Hz), 1.91 (m, 1H), 2.39 (bs,
1H), 2.86 (m, 1H), 2.99 (s, 3H), 3.21ꢀ3.42 (bs, 4H), 3.54
(m, 2H), 3.82 (bs, 1H), 3.99 (bs, 1H), 4.18 (m, 2H), 4.42
(m, 1H) 4.49ꢀ4.68 (bs, 4H), 5.25ꢀ5.53 (m, 4H), 5.75ꢀ
6.01 (bs, 2H).
3.11.8. Compound 10i
Yield 66.4%. 1H-NMR(CDCl3) d 1.26 (d, 3H, Jꢂ
Hz), 1.37 (d, 3H, Jꢂ
/
/6.9
/
Hz), 1.35 (d, 3H, Jꢂ
/
6.1 Hz), 1.90 (m, 1H), 2.50ꢀ
/2.69
(m, 2H), 3.05ꢀ3.33 (bs, 5H), 3.42 (m, 1H), 3.55ꢀ
/
/3.66
/
/
/
(bs, 2H), 3.70 (bs, 1H), 4.01 (m, 1H), 4.31 (m, 1H),
4.45ꢀ4.69 (bs, 4H), 5.26ꢀ5.55 (m, 4H), 5.75ꢀ5.99 (bs,
2H), 7.88 (d, 1H, Jꢂ6.2 Hz).
/
/
/
/
3.11.2. Compound 10c
Yield 64.3%. 1H-NMR(CDCl3) d 1.25 (d, 3H, Jꢂ
Hz), 1.35 (d, 3H, Jꢂ6.2 Hz), 2.06 (m, 1H), 2.39 (bs,
1H), 2.80 (m, 1H), 2.89 (s, 6H), 3.21ꢀ3.33 (bs, 2H),
3.38ꢀ3.54 (bs, 3H), 3.58 (m, 1H), 3.82 (bs, 1H), 3.99 (bs,
1H), 4.18 (m, 2H), 4.40 (m, 1H), 4.49ꢀ4.68 (bs, 4H),
5.25ꢀ5.53 (m, 4H), 5.70ꢀ5.99 (bs, 2H).
3.11.9. Compound 10j
Yield 62.4%. 1H-NMR(CDCl3) d 1.27 (d, 3H, Jꢂ
Hz), 1.36 (d, 3H, Jꢂ6.1 Hz), 1.99 (m, 1H), 2.15 (s, 3H),
2.59ꢀ2.67 (m, 1H), 3.03 (m, 1H), 3.08ꢀ3.39 (bs, 5H),
3.53 (m, 1H), 3.69 (bs, 1H), 3.80 (m, 1H), 4.01ꢀ4.15 (bs,
2H), 4.35 (m, 1H), 4.45ꢀ4.69 (bs, 6H), 5.16ꢀ5.55 (m,
6H), 5.70ꢀ5.99 (bs, 3H).
/7.1
/6.9
/
/
/
/
/
/
/
/
/
/
/
/
/
3.11.3. Compound 10d
Yield 72.5%. 1H-NMR(CDCl3) d 1.28 (d, 3H, Jꢂ
Hz), 1.37 (d, 3H, Jꢂ6.1 Hz), 1.98 (m, 1H), 2.30 (bs,
1H), 2.86 (m, 1H), 2.87 (s, 6H), 3.21ꢀ3.36 (bs, 2H),
3.40ꢀ3.55 (m, 3H), 3.60 (m, 1H), 3.82 (bs, 1H), 3.99 (bs,
1H), 4.18 (m, 2H), 4.42 (m, 1H), 4.49ꢀ4.68 (bs, 4H),
5.25ꢀ5.53 (m, 4H), 5.70ꢀ5.96 (bs, 2H).
3.11.10. Compound 10k
Yield 66.0%. 1H-NMR(CDCl3) d 1.26 (d, 3H, Jꢂ
/7.0
/6.9
/
Hz), 1.35 (d, 3H, Jꢂ
(m, 1H), 3.03 (m, 1H), 3.08ꢀ
(bs, 3H), 4.35 (m, 1H), 4.45ꢀ
(m, 8H), 5.75ꢀ6.03 (bs, 4H).
/
6.1 Hz), 1.98 (m, 1H), 2.59ꢀ
3.62 (bs, 7H), 4.01ꢀ
4.89 (bs, 8H), 5.08ꢀ
/
2.69
4.31
5.55
/
/
/
/
/
/
/
/
/
/
3.11.11. Compound 10l
Yield 65.1%. 1H-NMR(CDCl3) d 1.26 (d, 3H, Jꢂ
Hz), 1.38 (d, 3H, Jꢂ6.0 Hz), 2.36 (m, 1H), 2.51ꢀ2.85
(m, 10H), 3.18ꢀ3.24 (bs, 2H), 3.30ꢀ3.44 (bs, 4H), 3.69
(m, 1H), 3.85 (bs, 1H), 3.99 (bs, 1H), 4.19 (bs, 1H), 4.40
(m, 1H), 4.45ꢀ4.67 (bs, 4H), 5.25ꢀ5.53 (m, 4H), 5.75ꢀ
6.00 (bs, 2H).
3.11.4. Compound 10e
Yield 69.9%. 1H-NMR(CDCl3) d 1.26 (d, 3H, Jꢂ
Hz), 1.38 (d, 3H, Jꢂ6.0 Hz), 1.91 (m, 1H), 2.39 (bs,
1H), 3.21ꢀ3.52 (bs, 9H), 3.54ꢀ3.62 (bs, 6H), 3.82 (bs,
1H), 4.03 (bs, 1H), 4.18 (m, 2H), 4.42 (m, 1H), 4.49ꢀ4.68
(bs, 4H), 5.25ꢀ5.53 (m, 4H), 5.75ꢀ5.97 (bs, 2H).
/
7.0
/7.0
/
/
/
/
/
/
/
/
/
/
/
/
/

C.-H. Oh et al. / European Journal of Medicinal Chemistry 38 (2003) 841ꢀ
/
850
849
3.11.12. Compound 10m
Yield 68.0%. 1H-NMR(CDCl3) d 1.26 (d, 3H, Jꢂ
3.12.3. Compound 11d
Yield 25.2%. M.p. 155ꢀ
nm. 1H-NMR (D2O) d 1.14 (d, 3H, Jꢂ
3H, Jꢂ6.2 Hz), 1.73 (m, 1H), 2.57 (bs, 1H), 2.68 (s,
6H), 2.96ꢀ3.18 (bs. 4H), 3.21ꢀ3.44 (bs, 3H), 3.60 (bs,
1H), 3.83 (bs, 1H), 4.14 (bs, 2H), 4.49 (m, 1H). IR
(KBr): 3400, 1755, 1700, 1670, 1415 cmꢁ1
HRMS(FAB) Calc. for C20H32N5O6S: 470.2073. Found:
470.2079 [Mꢄ
H]ꢄ.
/6.9
/
171 8C (dec.). UV lmax: 298
7.0 Hz), 1.25 (d,
Hz), 1.35 (d, 3H, Jꢂ
(bs, 5H), 3.11 (m, 1H), 3.15ꢀ
/
6.2 Hz), 1.97 (m, 1H), 2.54ꢀ
/
2.80
3.46
/
/
3.26 (bs, 4H), 3.30ꢀ
/
/
(bs, 5H), 3.59 (bs, 1H), 3.94 (m, 1H), 4.12 (bs, 2H), 4.19
(m, 1H), 4.29 (m, 1H), 4.45ꢀ4.69 (bs, 6H), 5.26ꢀ5.55 (m,
6H), 5.75ꢀ6.01 (bs, 3H).
/
/
/
/
/
.
/
3.12. (1R,5S,6S)-6-[(1R)-hydroxyethyl]-2-[5-(2-
aminoethylcarbamoyl)pyrrolidin-3-ylthio]-1-
methylcarbapen-2-em-3-Carboxylic acid (11a)
3.12.4. Compound 11e
Yield 20.2%. UV lmax: 298 nm. H-NMR (D2O) d
1.06 (d, 3H, Jꢂ6.9 Hz), 1.13 (d, 3H, Jꢂ6.2 Hz), 1.93
(m, 1H), 2.46 (m, 1H), 3.03ꢀ3.30 (bs, 8H), 3.34ꢀ3.50
(bs, 2H), 3.54ꢀ3.69 (bs, 5H), 3.85 (bs, 2H), 3.99 (bs, 1H),
4.16 (bs, 1H), 4.45 (m, 1H). IR (KBr): 3390, 1720, 1700,
1680, 1591, 1400 cmꢁ1
HRMS(FAB) Calc. for
C22H34N5O7S: 512.2179. Found: 512.2185 [Mꢄ
H]ꢄ.
1
/
/
Compound 10a (0.31 g, 0.50 mmol) and 0.1 g of
/
/
Pd(OH)2 (10%) were dissolved in THFꢀ
/
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 (2ꢃ
combined filtrates were washed with ethyl ether (2ꢃ
/
10 mL). The
20
/
/
mL) and lyophilised 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 lyophilised again to give the title
3.12.5. Compound 11f
Yield 21.5%. UV lmax: 298 nm. H-NMR (D2O) d
1.06 (d, 3H, Jꢂ6.6 Hz), 1.13 (d, 3H, Jꢂ6.1 Hz), 1.87
(m, 1H), 2.46 (m, 1H), 2.51 (bs, 4H), 2.79ꢀ2.85 (m, 1H),
3.03ꢀ3.16 (bs, 4H), 3.28ꢀ3.44 (bs, 3H), 3.54ꢀ3.65 (bs,
1
/
/
/
compound 11a as an amorphous solid. Yield 21.8%.
/
/
/
1
M.p. 150ꢀ
(D2O) d 1.11 (d, 3H, Jꢂ
Hz), 1.78 (bs, 1H), 2.63 (m, 1H), 2.94 (m, 1H), 3.01ꢀ
(bs, 5H), 3.53ꢀ3.65 (bs, 2H), 3.70 (bs, 2H), 4.01 (m, 1H),
4.51 (bs, 1H). IR (KBr): 3480, 1745, 1666 cmꢁ1
HRMS(FAB) Calc. for C17H27N4O5S: 399.1702. Found:
399.1705 [Mꢄ
H]ꢄ.
The synthesis of compounds 11bꢀ
/
165 8C (dec.). UV lmax: 298 nm. H-NMR
4H), 3.69 (m, 1H), 3.85 (bs, 1H), 3.99 (bs, 1H), 4.16 (bs,
1H), 4.45 (m, 1H). IR (KBr): 3390, 1720, 1690, 1680,
/
6.8 Hz), 1.17 (d, 3H, Jꢂ
/
5.9
/3.48
1591,
1390
cmꢁ1
.
HRMS(FAB)
Calc.
for
H]ꢄ.
/
C22H34N5O6S2: 528.1951. Found: 528.1950 [Mꢄ
/
.
3.12.6. Compound 11g
Yield 21.9%. UV lmax: 298 nm. H-NMR (D2O) d
1.03 (d, 3H, Jꢂ6.7 Hz), 1.10 (d, 3H, Jꢂ6.2 Hz), 1.87
(m, 1H), 2.46 (m, 1H), 2.85 (m, 1H), 3.05ꢀ3.46 (bs,
1
/
/
m were carried out
/
/
by the same procedure as described for the preparation
of 11a.
/
10H), 3.54 (bs, 2H), 3.69 (m, 2H), 3.85 (bs, 1H), 4.02 (bs,
2H), 4.18 (m, 1H), 4.45 (m, 1H). IR (KBr): 3390, 1740,
1715, 1680, 1411 cmꢁ1
C22H35N6O6S: 511.2339. Found: 511.2347 [Mꢄ
.
HRMS(FAB) Calc. for
H]ꢄ.
3.12.1. Compound 11b
/
Yield 24.4%. M.p. 163ꢀ
nm. 1H-NMR (D2O) d 1.10 (d, 3H, Jꢂ
3H, Jꢂ6.2 Hz), 1.90 (m, 1H), 2.13 (bs, 1H), 2.86 (m,
1H), 2.97 (s, 3H), 3.03 (bs, 2H), 3.18ꢀ3.40 (bs, 4H), 3.54
(dd, 1H, Jꢂ5.2 and 5.6 Hz), 3.89 (bs, 1H), 4.04 (bs,
2H), 4.42 (m, 1H). IR (KBr): 3390 (NH), 1710, 1680,
1410, 1166 HRMS(FAB) Calc. for
cmꢁ1
C18H29N4O7S2: 477.1478. Found: 477.1488 [Mꢄ
H]ꢄ.
/
175 8C (dec.). UV lmax: 298
/
7.1 Hz), 1.16 (d,
3.12.7. Compound 11h
Yield 23.8%. UV lmax: 298 nm. H-NMR (D2O) d
1.07 (d, 3H, Jꢂ7.0 Hz), 1.17 (d, 3H, Jꢂ6.2 Hz), 1.87
(m, 1H), 2.45ꢀ2.59 (m, 1H), 2.88 (bs, 3H), 3.15ꢀ3.39
(bs, 4H), 3.44ꢀ3.69 (bs, 3H), 3.80 (m, 1H), 3.91 (m, 1H),
4.06ꢀ4.12 (bs, 2H), 4.45 (m, 1H). IR (KBr): 3400, 1730,
1680, 1586, 1400 cmꢁ1
C19H30N5O5S2: 472.1688. Found: 472.1692 [Mꢄ
1
/
/
/
/
/
/
/
/
.
/
/
. HRMS(FAB) Calc. for
/
H]ꢄ.
3.12.2. Compound 11c
Yield 29.4%. M.p. 145ꢀ
nm. 1H-NMR (D2O) d 1.10 (d, 3H, Jꢂ
3H, Jꢂ6.3 Hz), 1.93 (m, 1H), 2.13 (bs, 1H), 2.65 (s,
6H), 2.86 (m, 1H), 3.02 (bs, 2H), 3.21ꢀ3.44 (bs, 4H),
3.59 (dd, 1H, Jꢂ5.4 and 5.8 Hz), 3.87 (bs, 1H), 4.11 (bs,
2H), 4.42 (m, 1H). IR (KBr): 3390 (NH), 1715, 1690,
1400, 1166 HRMS(FAB) Calc. for
cmꢁ1
C19H32N5O7S2: 506.1743. Found: 506.1738 [Mꢄ
H]ꢄ.
3.12.8. Compound 11i
Yield 24.3%. M.p. 148ꢀ
/
168 8C (dec.). UV lmax: 298
/
162 8C (dec.). UV lmax: 298
/
7.0 Hz), 1.16 (d,
nm. 1H-NMR (D2O) d 1.03 (d, 3H, Jꢂ
/
6.8 Hz), 1.11 (d,
2.59 (m, 1H), 2.95ꢀ
3.24 (bs, 2H), 3.27ꢀ3.40 (bs, 2H),
3.66 (bs, 2H), 3.70 (bs, 1H), 4.16 (m, 2H), 4.41 (m,
1H), 7.68 (d, 1H Jꢂ6.2 Hz). IR (KBr): 3397, 1756,
1685, 1655, 1401 cmꢁ1
HRMS(FAB) Calc. for
C18H28N5O5S: 426.1811. Found: 426.1815 [Mꢄ
H]ꢄ.
/
3H, Jꢂ
3.10 (bs, 2H), 3.12ꢀ
3.55ꢀ
/
6.2 Hz), 1.56 (m, 1H), 2.50ꢀ
/
/
/
/
/
/
/
/
.
.
/
/

850
C.-H. Oh et al. / European Journal of Medicinal Chemistry 38 (2003) 841ꢀ850
/
3.12.9. Compound 11j
crude residue, which was used without further purifica-
tion. The 11lQ was prepared by the deprotection
procedure described for 11a. Yield 20.1%. UV lmax:
Yield 22.2%. M.p. 196ꢀ
nm. 1H-NMR (D2O) d 1.10 (d, 3H, Jꢂ
3H, Jꢂ6.3 Hz), 1.60 (m, 1H), 2.05 (s, 3H), 2.59ꢀ
(m, 1H), 2.99 (m, 1H), 3.08ꢀ3.39 (bs, 4H), 3.41ꢀ3.53 (m,
2H), 3.59 (bs, 1H), 3.73ꢀ3.89 (bs, 1H), 4.01ꢀ4.15 (bs,
/
205 8C (dec.). UV lmax: 298
7.0 Hz), 1.18 (d,
2.67
/
1
/
/
298 nm. H-NMR (D2O) d 1.02 (d, 3H, Jꢂ
1.07 (d, 3H, Jꢂ6.3 Hz), 1.85 (m, 1H), 2.61ꢀ
2H), 2.88ꢀ3.00 (bs, 3H), 3.01 (s, 3H), 3.10ꢀ3.28 (bs,
3H), 3.35ꢀ3.44 (bs, 3H), 3.55ꢀ3.68 (bs, 5H), 3.73 (m,
1H), 3.83ꢀ3.88 (bs, 2H), 4.03 (bs, 1H), 4.45 (m, 1H). IR
(KBr): 3470, 1730, 1685, 1580, 1425 cmꢁ1
/7.0 Hz),
/
/
/
/2.70 (m,
/
/
/
/
2H), 4.45 (m, 1H). IR (KBr): 3490, 1740, 1700, 1650,
1400 cmꢁ1. HRMS(FAB) Calc. for C19H30N5O5S:
440.1968. Found: 440.1967 [Mꢄ
/
/
/
/
H]ꢄ.
.
Compound 11mQ was also prepared as described for
the preparation of 11lQ.
3.12.10. Compound 11k
Yield 20.0%. M.p. 193ꢀ
1
Yield 24.7%. UV lmax: 298 nm. H-NMR (D2O) d
/
205 8C (dec.). UV lmax: 298
nm. 1H-NMR (D2O) d 1.02 (d, 3H, Jꢂ
/
7.3 Hz), 1.10 (d,
1.04 (d, 3H, Jꢂ
(m, 1H), 2.65ꢀ2.69 (bs, 1H), 3.01 (s, 3H), 3.05ꢀ
4H), 3.25ꢀ3.39 (bs, 4H), 3.63ꢀ3.78 (m, 2H), 3.85 (m,
/
7.1 Hz), 1.09 (d, 3H, Jꢂ/6.4 Hz), 1.88
3H, Jꢂ
/
6.4 Hz), 1.88 (m, 1H), 2.55ꢀ
/
2.61 (m, 1H), 3.10ꢀ
/
/
/3.19 (bs,
3.45 (bs, 6H), 3.55 (m, 1H), 3.88 (bs, 2H), 4.03 (bs, 2H),
4.45 (m, 1H). IR (KBr): 3980, 1710, 1640, 1580, 1405
cmꢁ1. HRMS(FAB) Calc. for C18H29N6O5S: 441.1920.
/
/
2H), 4.01 (m, 2H), 4.26 (m, 1H), 4.45 (m, 1H). IR (KBr):
3370, 1755, 1690, 1580, 1430 cmꢁ1
.
Found: 441.1920 [Mꢄ
H]ꢄ.
/
3.12.11. Compound 11l
Yield 20.1%. UV lmax: 298 nm. H-NMR (D2O) d
0.98 (d, 3H, Jꢂ7.1 Hz), 1.06 (d, 3H, Jꢂ6.4 Hz), 1.78
(m, 1H), 2.65ꢀ2.79 (bs, 5H), 2.90ꢀ3.01 (bs, 2H), 3.05ꢀ
3.38 (bs, 5H), 3.55ꢀ3.60 (bs, 3H), 3.65 (bs, 1H), 3.80ꢀ
References
1
/
/
[1] For a recent review on the current state of carbapenem
antibiotics, see: S. Coultion, E. Hunt, in: G.P. Ellis, D.K.
Luscombe (Eds.), Progress in Medicinal Chemistry, vol. 33,
/
/
/
/
/
Elsevier, 1996, pp 99ꢀ
[2] (a) H. Hanaki, H. Akagi, S. Nomura, N. Unemi, J. Antibiot. 49
(1996) 402ꢀ404;
(b) O.K. Kim, Y. Udea, M. Mansuri, J.W. Russel, Bioorg. Med.
Chem. Lett. 7 (1997) 1945ꢀ1950.
/
145.
3.88 (bs, 2H), 4.03 (bs, 2H), 4.45 (m, 1H). IR (KBr):
3470, 1730, 1685, 1580, 1425 cmꢁ1. HRMS(FAB) Calc.
/
for C21H33N4O5S2: 485.1892. Found: 485.1894 [Mꢄ
/
H]ꢄ.
/
[3] (a) L.C. Waddel, R.W. Ratcliffe, S.P. Szumiloski, K.J. Wildonger,
J. Kohler Huber, G.G. Hamond, Bioorg. Med. Chem. Lett. 5
3.12.12. Compound 11m
(1995) 1427ꢀ
(b) H. Shinagawa, H. Yamaga, H. Houchigai, Y. Sumita, M.
Sunaga, Bioorg. Med. Chem. 5 (1997) 601ꢀ621.
[4] Y. Fukasawa, T. Okuda, J. Antibiot. 43 (1990) 314ꢀ
[5] M. Sunagawa, H. Matsumure, T. Inoue, M. Fukasawa, M. Kato,
J. Antibiot. 43 (1990) 519ꢀ532.
[6] T. Miyadera, T. Sugimura, T. Hasimoto, T. Tanaka, K. Iino, S.
Sugawara, J. Antibiot. 36 (1983) 1034ꢀ1039.
[7] C.-H. Oh, J.-H. Cho, J. Antibiot. 47 (1994) 126ꢀ
[8] K.-H. Nam, C.-H. Oh, J.K. Cho, K.-S. Lee, J.-H. Cho, Arch.
Pharm. Pharm. Med. Chem. 329 (1996) 289ꢀ291.
[9] C.-H. Oh, Y.H. Ham, K.-S. Lee, J.-H. Cho, Arch. Pharm. Pharm.
Med. Chem. 330 (1997) 268ꢀ270.
[10] 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) 59ꢀ67.
[11] 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) 152ꢀ158.
[12] 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) 200ꢀ206.
[13] C.-H. Oh, H.-W. Cho, J.-H. Cho, Eur. J. Med. Chem. 37 (2002)
743ꢀ754.
/
1432;
Yield 16.9%. M.p. 166ꢀ
nm. 1H-NMR (D2O) d 1.02 (d, 3H, Jꢂ
3H, Jꢂ6.4 Hz), 1.88 (m, 1H), 2.45ꢀ2.49 (m, 1H), 2.60ꢀ
2.69 (bs, 4H), 3.07ꢀ3.15 (bs, 4H), 3.25ꢀ3.39 (bs, 4H),
3.66ꢀ3.78 (m, 2H), 3.89 (m, 2H), 4.03 (m, 2H), 4.26 (m,
/
175 8C (dec.). UV lmax: 298
/
7.1 Hz), 1.08 (d,
/
/
320.
/
/
/
/
/
/
/
1H), 4.45 (m, 1H). IR (KBr): 3370, 1755, 1690, 1580,
1430 cmꢁ1. HRMS(FAB) Calc. for C21H34N5O5S:
/
/
128.
468.2281. Found: 468.2280 [Mꢄ
H]ꢄ.
/
/
3.13. (1R,5S,6S)-6-[(1R)-hydroxyethyl]-2-[5-(2-(1-
methylthiomorpholin-1yl)ethylcarbamoyl)]pyrrolidin-3-
ylthio]-1-methylcarbapen-2-em-3-Carboxylic acid
(11lQ)
/
/
/
A mixture of 10l (1.2 g, 2.0 mmol) and methyl iodide
(4.1 g, 40.0 mmol) in acetone (20 mL) was stirred at r.t.
for 20 h. Evaporation of the solvent in vacuo gave a
/
/