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

Article abstract of DOI:10.1016/S0223-5234(03)00116-8

The synthesis of a new series of 1-methylcarbapenems having the substituted thiazolopyrrolidine moiety is described. Their in vitro antibacterial activities against both gram-positive and gram-negative bacteria were tested and the effect of substituent on

Full text of DOI:10.1016/S0223-5234(03)00116-8

European Journal of Medicinal Chemistry 38 (2003) 751ꢀ758
/
www.elsevier.com/locate/ejmech
Short communication
Synthesis and antibacterial activity of 1b-methyl-2-[5-(N-substituted-
2-hydroxy iminoethyl)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, P.O. Box 131, Cheongryang, Seoul 130-650, South Korea
b Hawon Pharm. Co., Seoul 135-080, South Korea
Received 7 January 2003; received in revised form 9 May 2003; accepted 9 May 2003
Abstract
The synthesis of a new series of 1-methylcarbapenems having the substituted thiazolopyrrolidine moiety 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 investigated. In particular, compounds 12b and 12k showed the most potent antibacterial activity.
´
# 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: 1b-Methylcarbapenem; b-Lactam antibiotics
1. Introduction
potent antibacterial activity, and a large number of
derivatives have been synthesised and investigated [7ꢀ
13].
We conceived that introduction of an additional
oxime moiety into the pyrrolidine side chain was
responsible for the improvements, because the com-
pounds having oxime moiety has shown to enhance drug
activity in general.
/
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 [1], and a large number of
derivatives have been synthesised and investigated with
enthusiasm. Among those compounds, panipenem [2]
and meropenem [3] were the first to be successfully
launched in the market and clinical evaluations are in
progress for S-4661 [4], BO-2727 [5] and DX-8739 [6],
which have enhanced metabolic stability to renal
dehydropeptidase-1 (DHP-1) due to the introduction
of a 1b-methyl group into the carbapenem skeleton. We
were also interested in this pyrroldin-3-ylthio group and
reported that the carbapenem compounds having a
pyrrolidine-3-ylthio group at the C-2 position in the
carbapenem skeleton are noted for their broad and
In this paper, we described the synthesis and
structureꢀactivity relationships of the lb-methylcarba-
/
penems having a 5?-oxime substituted pyrrolidine-3?-
ylthio group as a C-2 side chain and our approach for
improvement of antibacterial activity of the carbape-
nems was discussed.
2. Results and discussion
2.1. Chemistry
Our general synthetic route leading to new carbape-
nems involved the preparation of appropriately pro-
* Corresponding author. Tel.: ꢁ82-2-958-5189.
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)00116-8

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C.-H. Oh et al. / European Journal of Medicinal Chemistry 38 (2003) 751ꢀ758
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Scheme 1. (i) MsCl, TEA, CH2Cl2; (ii) TrSH, NaH, DMF; (iii) LiBH4, EtOH/THF; (iv) MsCl, TEA, CH2Cl2; (v) NaCN, DMSO; (vi) NH2OH×
/
HCl,
EtOH; (vii) RCOCl, TEA or p-nitrophenyl chloroformate, TEA, CH2Cl2 and amine, ETOH; (viii) TFA, Et3SiH, CH2Cl2.
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-
(3-Substituted-2-hydroxyiminoethyl)pyrrolidine deriva-
8m with trifluoroacetic acid in the presence of triethylsi-
lane.
Finally, the reaction of 10 [9] with thiols (9aꢀ
the presence of diisopropylethylamine provided the
corresponding 2-substituted carbapenem (11aꢀ11m).
/
9m) in
/
tives (9aꢀ9m) were prepared by the sequence shown in
/
Deprotection of these compounds by catalytic hydro-
genation gave the crude products, which were purified
Scheme 1. N-Protected proline methyl ester was con-
verted to the O-mesylate 2 by treatment of mesyl
chloride and subsequently treated with sodium triphe-
nylmethylthioate, which was generated in situ from
triphenylmethylmercaptan and sodium hydride in
DMF, to provide 3 with inversion of the C-4 config-
uration. 3 was reduced with lithium borohydride in
THFꢀEtOH and subsequently mesylated to give 5. The
/
treatment of the mesylate 5 with sodium cyanide in
DMSO gave the cyano compound 6, which was
successfully converted into N-hydroxyacetamidine 7 by
reaction of hydroxylamine. Treatment of 7 with acetyl
chloride, cyclopropyl chloride, allyl chloroformate and
methyl chloroformate afforded the corresponding N-
acetylated products, 8a, 8b, 8c and 8d. Carbamoylation
of amine was carried out by a conventional method
using p-nitrophenyl chloroformate to give urea type
compounds 8eꢀ
mercaptans (9aꢀ
/
8m. Deprotection of the trityl group to
Scheme 2. (i) Diisopropylethylamine, 9aꢀ9m; (ii) Pd(OH)2, H2.
/
/
9m) were achieved by treatment of 8aꢀ
/

C.-H. Oh et al. / European Journal of Medicinal Chemistry 38 (2003) 751ꢀ
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758
753
by HP-20 column to give the pure carbapenems (12aꢀ
/
12m) (Scheme 2).
2.2. Biological assay
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 mLꢂ1
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
for 18ꢀ20 h. The MICs of a compound was defined as
/
the lowest concentration that visibly inhibited growth.
2.2.2. Determination of susceptibility to renal DHP-1
The relative hydrolysis rate of carbapenems by
porcine renal DHP-1 was determined, taking the initial
hydrolysis rate of imipenem as 1.0. Partially purified
porcine DHP-1 (final concentration, 0.3 U mLꢂ1) 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
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.
2.2.3. Antibacterial activity studies
The in vitro antibacterial activities of the new
carbapenems (12aꢀ12m) prepared above against gram-
/
positive and -negative bacteria are listed in Table 1. For
comparison, the MIC values of imipenem and merope-
nem are also listed. All the compounds (12aꢀ12m)
/
displayed superior or similar antibacterial activities
against gram-positive to meropenem, and against
gram-negative bacteria except Pseudomonas aeruginosa
to imipenem.
The effects of substituent on the pyrrolidine ring were
investigated. The cyclic urea substituted compounds
(12iꢀ
both gram-positive and -negative bacteria including P.
aeruginosa than that of aliphatic ureas (12eꢀ12g).
Comparing the compounds 12iꢀ12m having cyclic urea
/
12m) showed more improved activity against
/
/
moieties on the pyrrolidine ring showed slight differ-
ences in the antibacterial activities against gram-positive
and -negative bacteria. As expected, the piperazine urea
compound 12k exhibited the most potent and well-
balanced activity. Furthermore, we observed that the
thiomorpholine urea 12j is more potent than the
morpholine urea 12i.
The stability to DHP-1 of most compounds was tested
and all the compounds were more stable than merope-
nem.

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3. Experimental
3.3. (2S,4S)-2-Hydroxymethyl-4-tritylthio-1-
(allyloxycarbonyl)pyrrolidine (4)
Melting point (m.p.): Thomas Hoover apparatus,
Packard 8451A
Elmer
16F-PC FT-IR. NMR spectra: Varian Gemini 300
spectrometer and tetramethylsilane (TMS), as an inter-
nal standard. The mass spectrometry system was based
on an HP 5989A MS Engine (Palo Alto, CA) mass
spectrometer with an HP Model 59987A.
uncorrected. UV spectra: Hewlettꢀ
/
To a solution of 3 (107.3 g, 0.22 mol) in THF (800
mL) was added slowly LiBH4 (4.79 g, 0.22 mol) at 0 8C
and was stirred for 25 h at room temperature. The
mixture was diluted with H2O (200 mL), 1N-HCl (200
mL) and extracted with ethyl acetate (800 mL). The
organic layer was dried over anhydrous Na2SO4, con-
centrated and the resulting residue was purified by silica
UVꢀVis spectrophotometer. IR spectra: Perkinꢀ
/
/
gel column chromatography to give 4 (79.3 g, 78.5%) as
1
3.1. (2S,4R)-4-Mesyloxy-1-
(allyloxycarbonyl)pyrrolidine-2-carboxylic acid methyl
ester (2)
a pale yellow oil. H-NMR (CDCl3) dꢃ/1.98 (m, 1H),
2.75ꢀ/2.82 (m, 2H), 3.01 (m, 1H), 3.55 (bs, 2H), 3.78 (m,
1H), 4.55 (d, 3H, Jꢃ
/
5.9 Hz), 5.25 (m, 3H), 5.90 (m,
1H), 7.27 (m, 9H), 7.47 (m, 6H). 13C-NMR (CDCl3):
36.1, 41.0, 53.2, 53.9, 60.9, 66.6, 67.2, 67.6, 117.9, 127.3,
128.5, 129.9, 132.9, 145.0, 156.8. IR (KBr): 3450, 2950,
A solution of 1 [14] (94.0 g, 0.41 mol) and triethyla-
mine (65.0 mL, 0.49 mol) in dry CH2Cl2 (600 mL) was
cooled to 0 8C under nitrogen and treated with metha-
nesulfonyl chloride (56.0 g, 0.49 mol). The mixture was
stirred at 0 8C for 1 h, diluted with CH2Cl2 (500 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 2
1735 cmꢂ1
.
3.4. (2S,4S)-2-Mesyloxymethyl-4-tritylthio-1-
(allyloxycarbonyl)pyrrolidine (5)
A solution of 4 (68.9 g, 0.15 mol) and triethylamine
(24.2 mL, 0.18 mol) in dry CH2Cl2 (400 mL) was cooled
to 0 8C under nitrogen and treated with methanesulfonyl
chloride (20.6 g, 0.18 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 5
1
(117.1 g, 93.2%) as a pale yellow oil. H-NMR (CDCl3)
dꢃ
3.80 (2s, 3H), 3.82ꢀ
2H, Jꢃ5.8 Hz), 5.25ꢀ
/
2.27 (m, 1H), 2.65 (m, 1H), 3.03 (s, 3H), 3.77 and
3.97 (m, 2H), 4.42 (m, 1H), 4.57 (d,
5.40 (m, 3H), 5.88 (m, 1H). 13C-
/
/
/
NMR: 36.7, 37.8, 39.0, 52.9, 57.5, 66.6, 78.5, 117.9,
132.8, 154.5, 172.6. IR (KBr): 2970, 1745, 1666, 1358
cmꢂ1
.
1
(76.3 g, 94.8%) as a pale yellow oil. H-NMR (CDCl3)
3.2. (2S,4S)-4-Tritylthio-1-
(allyloxycarbonyl)pyrrolidine-2-carboxylic acid methyl
ester (3)
dꢃ
/
1.91 (bs, 1H), 2.11 (bs, 1H), 2.75ꢀ2.82 (bs, 2H), 2.99
/
(s, 3H), 3.95 (bs, 1H), 4.01 (m, 1H), 4.22 (bs, 1H), 4.55
(bs, 3H), 5.31 (m, 2H), 5.91 (m, 1H), 7.27 (m, 9H), 7.48
(m, 6H). 13C-NMR (CDCl3): 31.9, 35.1, 37.5, 41.4, 52.9,
55.8, 66.2, 67.8, 69.4, 117.9, 127.3, 128.5, 129.6, 133.0,
To a stirred solution of triphenylmethylmercaptan
(80.0 g, 0.29 mol) in dry DMF (600 mL) was added
dropwise sodium hydride (11.6 g, 0.29 mol, 60% oil
suspension) at 0 8C and was stirred for 1 h at room
temperature. To the resulting solution was added 2 (76.6
g, 0.25 mol) solution in dry DMF (150 mL) at 0 8C and
was stirred for 3 h at room temperature. The reaction
mixture was poured into cold dilute HCl and extracted
with ethyl acetate. The organic layer was successively
washed with water and dried over anhydrous Na2SO4.
Evaporation of the solvent in vacuo gave a crude
residue, which was purified by silica gel column
chromatography to give 3 (100.6 g, 82.5%) as a pale
144.9, 154.7. IR (KBr): 2940, 1682, 1380 cmꢂ1
.
3.5. (2S,4S)-2-Cyanomethyl-4-tritylthio-1-
(allyloxycarbonyl)pyrrolidine (6)
A mixture of 5 (59.2 g, 0.11 mol) and sodium cyanide
(10.8 g, 0.22 mol) in DMSO (300 mL) was heated at
75 8C for 5 h. The reaction mixture was poured into ice
water and extracted with ethyl acetate (2ꢄ
The organic layer was successively washed with water
(2ꢄ200 mL), 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 (45.9 g, 89.1%) as a pale
yellow oil. 1H-NMR (CDCl3) dꢃ
1H), 2.82 (d, 2H), 2.85ꢀ
/
300 mL).
/
yellow oil. 1H-NMR (CDCl3) dꢃ
1H), 3.16 (bs, 1H), 3.54 (bs, 1H), 3.77 and 3.80 (2s, 3H),
/2.01 (m, 1H), 2.55 (m,
3.97 (m, 1H), 4.42 (m, 1H), 4.55 (d, 2H, Jꢃ
/
5.5 Hz), 5.26
/
1.88 (m, 1H), 2.19 (m,
3.01 (m, 2H), 3.88 (m, 1H), 4.15
5.9 Hz), 5.29 (m, 2H), 5.88 (m,
(m, 2H), 5.98 (m, 1H) 7.23 (m, 9H), 7.48 (m, 6H). 13C-
NMR (CDCl3): 37.1, 38.2, 42.0, 52.7, 58.5, 66.3, 67.8,
117.6, 127.3, 128.3, 129.9, 132.9, 144.9, 153.5, 172.6. IR
/
(bs, 1H), 4.55 (d, 2H, Jꢃ
/
1H), 7.27 (m, 9H), 7.47 (m, 6H). 13C-NMR (CDCl3):
22.7, 38.1, 39.2, 41.4, 53.0, 53.8, 66.3, 67.8, 117.6, 118.9,
(KBr): 2950, 1765, 1708 cmꢂ1
.

C.-H. Oh et al. / European Journal of Medicinal Chemistry 38 (2003) 751ꢀ
/
758
755
127.4, 128.5, 129.9, 132.9, 144.9, 154.7. IR (KBr): 2940,
2248, 1700 cmꢂ1
2.63ꢀ
/
2.89 (bs, 3H), 3.83 (bs, 1H), 4.55 (bs, 2H), 5.25ꢀ
/
.
5.34 (m, 3H), 5.87 (m, 1H), 7.24 (m, 9H), 7.45 (m, 6H).
13C-NMR (CDCl3): 11.2, 14.1, 36.3, 38.5, 41.6, 53.1,
55.4, 66.2, 67.8, 117.8, 127.2, 128.5, 129.9, 132.1, 144.7,
154.9, 156.5, 179.8. IR (KBr): 3420, 2930, 1720, 1670,
1490 cmꢂ1
8d: Yield 83.5%. 1H-NMR (CDCl3) dꢃ
2.28 (bs, 1H), 2.54 (m, 1H), 2.60ꢀ2.72 (bs, 3H), 3.85 (bs,
3.6. (2S,4S)-2-(N-Hydroxyacetamidine)-4-tritylthio-1-
(allyloxycarbonyl)pyrrolidine (7)
.
To a solution of 6 (23.4 g, 0.05 mol) and hydro-
xylamine hydrochloride (10.4 g, 0.15 mol) in EtOH (250
mL) was added slowly a solution of Na2CO3 (15.9 g,
0.15 mol) in water (70 mL) at room temperature and
stirred for 20 h at 60 8C. The mixture was diluted with
H2O (200 mL) and then was neutralised with 6N-HCl,
diluted with ethyl acetate (300 mL), and washed with
brine. The organic layer was dried over anhydrous
Na2SO4, which was purified by silica gel column
chromatography to give 7 (19.3 g, 77.1%) as a pale
/1.84 (bs, 1H),
/
1H), 3.90 (s, 3H), 4.50 (bs, 2H), 5.25 (m, 3H), 5.86 (m,
1H), 7.24 (m, 9H), 7.46 (m, 6H). 13C-NMR (CDCl3):
36.1, 38.4, 41.6, 50.8, 53.1, 55.6, 66.1, 67.8, 117.6, 127.3,
128.5, 129.7, 133.1, 145.2, 152.5, 154.5, 169.5. IR (KBr):
3430, 2930, 1720, 1690, 1510 cmꢂ1
.
3.8. (2S,4S)-2-(3-Aminocarbonylamino-2-
hydroxyimino)ethyl-4-tritylthio-1-
(allyloxycarbonyl)pyrrolidine (8e)
yellow oil. 1H-NMR (CDCl3) dꢃ
2H), 2.73ꢀ2.82 (bs, 3H), 3.88 (bs, 1H), 4.55 (d, 2H, Jꢃ
/1.81 (bs, 1H), 2.19 (m,
/
/
5.9 Hz), 4.71 (bs, 1H), 5.22 (m, 2H), 5.88 (m, 1H), 7.23
(m, 9H), 7.47 (m, 6H), 8.55 (br, 1H). 13C-NMR
(CDCl3): 36.6, 38.4, 41.7, 53.1, 53.9, 55.6, 66.1, 67.8,
117.7, 127.2, 128.5, 129.9, 133.1, 145.1, 152.1, 154.9. IR
To a solution of 7 (1.00 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
ammonia water (10 mL) and stirred for 1 h at room
temperature. The reaction mixture was neutralised with
6N-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 8e (0.89 g, 81.5%) as a
(KBr): 3476, 3360, 2940, 1694, 1592 cmꢂ1
.
3.7. (2S,4S)-2-(3-Allyloxycarbonylamino-2-
hydroxyimino)ethyl-4-tritylthio-1-
(allyloxycarbonyl)pyrrolidine (8a)
To a solution of 7 (1.00 g, 2.0 mmol) and triethyla-
mine (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 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-
pale yellow oil. 1H-NMR (CDCl3) dꢃ
2.19 (m, 1H), 2.27 (m, 1H), 2.63ꢀ2.99 (bs, 3H), 3.84 (bs,
/1.82 (bs, 1H),
/
1H), 4.55 (bs, 2H), 4.72 (bs, 2H), 5.26 (m, 3H), 5.85 (m,
1H), 7.24 (m, 9H), 7.45 (m, 6H). 13C-NMR (CDCl3):
36.1, 38.4, 41.6, 53.1, 55.6, 66.1, 67.8, 117.7, 127.3,
128.6, 129.5, 133.2, 145.0, 152.5, 154.9, 158.7. IR (KBr):
1
phy to give 8a (1.03 g, 88.3%) as a pale yellow oil. H-
NMR (CDCl3) dꢃ
1H), 2.63ꢀ2.85 (bs, 3H), 3.88 (bs, 1H), 4.55 (bs, 2H),
4.72 (d, 2H, Jꢃ 5.98
/
1.82 (bs, 2H), 2.19 (m, 1H), 2.24 (m,
/
/
5.9 Hz), 5.20ꢀ
/
5.44 (m, 5H), 5.85ꢀ
/
3430, 2920, 1710, 1660 cmꢂ1
.
(m, 2H), 7.23 (m, 9H), 7.47 (m, 6H). 13C-NMR (CDCl3):
36.1, 38.4, 41.6, 53.1, 55.6, 66.1, 67.8, 68.1, 117.6, 127.3,
128.5, 129.7, 133.2, 145.0, 152.1, 154.9, 157.3. IR (KBr):
Compounds 8fꢀ8m were also prepared as described
/
for the preparation of 8e using the corresponding
amines.
3450, 2940, 1700, 1644, 1592 cmꢂ1
.
8f: Yield 76.2%. 1H-NMR (CDCl3) dꢃ
/
1.70 (bs, 1H),
2.90 (bs, 3H), 2.88 (d,
4.7 Hz), 3.83 (bs, 1H), 4.49 (bs, 2H), 5.26 (m,
8b, 8c and 8d were also prepared as described for the
preparation of 8a using the corresponding carbonyl
chlorides.
2.19 (bs, 1H), 2.27 (m, 1H), 2.63ꢀ
/
3H, Jꢃ
/
3H), 5.88 (m, 1H), 6.44 (bs, 1H), 7.27 (m, 9H), 7.47 (m,
6H). 13C-NMR (CDCl3): 30.1, 36.3, 38.5, 41.6, 53.1,
55.4, 60.8, 66.2, 67.8, 117.8, 127.2, 128.5, 129.9, 132.1,
144.9, 154.2, 154.9, 157.5. IR (KBr): 3410, 2940, 1710,
8b: Yield 82.5%. 1H-NMR (CDCl3) dꢃ
/
1.82 (bs, 1H),
2.03 (s, 3H), 2.19 (m, 1H), 2.54 (m, 1H), 2.63ꢀ2.85 (bs,
/
3H), 3.88 (bs, 1H), 4.55 (bs, 2H), 5.25 (m, 3H), 5.90 (m,
1H), 7.23 (m, 9H), 7.47 (m, 6H). 13C-NMR (CDCl3):
18.8, 36.3, 38.4, 41.6, 53.1, 55.6, 66.1, 67.8, 117.6, 127.3,
128.5, 129.7, 133.1, 145.0, 152.1, 154.9, 167.3. IR (KBr):
1660, 1510 cmꢂ1
8g: Yield 75.1%. 1H-NMR (CDCl3) dꢃ
2.18 (m, 1H), 2.47 (m, 1H), 2.63ꢀ2.89 (bs, 3H), 3.01 (s,
.
/1.87 (bs, 1H),
/
3430, 2920, 1740, 1674, 1512 cmꢂ1
8c: Yield 87.8%. 1H-NMR (CDCl3) dꢃ
1.12 (bs, 2H), 1.82 (bs, 1H), 2.29 (m, 1H), 2.54 (m, 1H),
.
6H), 3.84 (bs, 1H), 4.55 (bs, 2H), 5.04 (bs, 1H), 5.26 (m,
2H), 5.85 (m, 1H), 7.24 (m, 9H), 7.45 (m, 6H). 13C-
NMR (CDCl3): 35.1, 36.3, 38.5, 41.6, 53.1, 55.4, 60.8,
/
0.82 (bs, 3H),

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C.-H. Oh et al. / European Journal of Medicinal Chemistry 38 (2003) 751ꢀ758
/
66.2, 67.8, 117.8, 127.2, 128.5, 129.9, 132.1, 144.9, 154.1,
154.9, 157.5. IR (KBr): 3410, 2930, 1710, 1660, 1510
3.9. (2S,4S)-2-(3-Allyloxycarbonylamino-2-
hydroxyimino)ethyl-4-mercaptan-1-
(allyloxycarbonyl)pyrrolidine (9a)
cmꢂ1
.
8h: Yield 74.9%. 1H-NMR (CDCl3) dꢃ
2.19 (m, 1H), 2.27 (m, 1H), 2.63ꢀ2.94 (bs, 3H), 2.99 (t,
2H, Jꢃ5.1 Hz), 3.55 (t, 2H, Jꢃ5.1 Hz), 3.84 (bs, 1H),
4.55 (bs, 2H), 5.16ꢀ5.33 (m, 3H), 5.85 (m, 1H), 7.24 (m,
/
1.85 (bs, 1H),
To a solution of 8a (0.59 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 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 concentrated
in vacuo to give a residue, which was purified by silica
/
/
/
/
9H), 7.45 (m, 6H). 13C-NMR (CDCl3): 36.1, 38.5, 41.6,
48.5, 53.1, 55.4, 62.8, 66.2, 67.8, 117.8, 127.2, 128.5,
129.9, 132.1, 144.9, 154.1, 154.9, 157.7. IR (KBr): 3550,
3410, 2930, 1710, 1670 cmꢂ1
.
1
8i: Yield 71.3%. H-NMR (CDCl3) dꢃ
/
1.84 (bs, 1H),
2.72 (bs, 3H), 2.91(m,
3.82 (bs, 4H), 4.56 (bs,
5.35 (m, 3H), 5.83 (m, 1H), 7.24 (m, 9H), 7.44
gel column chromatography to give 9a (0.21 g, 61.2%) as
1
2.26 (m, 1H), 2.45 (m, 1H), 2.63ꢀ
1H), 3.51ꢀ3.57 (bs, 4H), 3.71ꢀ
2H), 5.15ꢀ
/
a pale yellow oil. H-NMR (CDCl3) dꢃ
/
1.89 (bs, 2H),
3.18 (bs, 1H),
4.01 (bs, 1H), 4.55 (bs, 2H), 4.72 (bs, 2H), 5.26ꢀ5.55 (m,
4H), 5.85ꢀ
5.93 (m, 2H). 13C-NMR (CDCl3): 33.3, 38.9,
41.9, 53.7, 55.6, 67.8, 68.2, 117.6, 133.2, 152.1, 159.3,
159.9. IR (KBr): 3450, 2920, 1700, 1660, 1410 cmꢂ1
The synthesis of compounds 9bꢀ9m were carried out
2.40ꢀ
/
2.55 (bs, 3H), 2.84 (bs, 1H), 3.05ꢀ
/
/
/
/
/
(m, 6H). 13C-NMR (CDCl3): 36.3, 38.8, 41.6, 47.1, 53.1,
55.5, 64.6, 66.2, 67.7, 117.8, 127.4, 128.5, 129.9, 133.2,
145.0, 154.1, 154.9, 156.6. IR (KBr): 3420, 2940, 1700,
/
.
/
1660, 1510 cmꢂ1
.
by the same procedure as described for the preparation
of 9a and was used without the further purification.
1
8j: Yield 73.8%. H-NMR (CDCl3) dꢃ
2.23 (m, 1H), 2.37 (m, 1H), 2.69ꢀ2.76 (bs, 6H), 2.96 (m,
2H), 3.74ꢀ3.84 (bs, 4H), 4.55 (bs, 2H), 5.16ꢀ5.33 (m,
/1.89 (bs, 1H),
/
/
/
3.10. Allyl(1R,5S,6S)-6-[(1R)-hydroxyethyl]-3-[5-
(3-allyloxycarbonylamino-2-hydroxyimino) ethyl-1-yl]-
1-(allyloxycarbonyl)pyrrolidin-3-ylthio-1-
3H), 5.85 (m, 1H), 7.24 (m, 9H), 7.44 (m, 6H). 13C-
NMR (CDCl3): 27.6, 36.7, 38.8, 41.6, 47.1, 53.1, 55.5,
66.2, 67.7, 117.8, 127.4, 128.5, 129.9, 133.1, 144.9, 154.1,
154.9, 156.5. IR (KBr): 3420, 2940, 1700, 1660, 1510
methylcarbapen-2-em-3-carboxylate (11a)
cmꢂ1
8k: Yield 72.9%. 1H-NMR (CDCl3) dꢃ
2.25ꢀ2.37 (m, 1H), 2.63ꢀ2.74 (bs, 2H), 2.95 (m, 2H),
3.51ꢀ3.57 (bs, 8H), 3.84 (bs, 1H), 4.55 (bs, 2H), 5.14ꢀ
5.35 (m, 3H), 5.85 (m, 1H), 7.24 (m, 9H), 7.45 (m, 6H).
13C-NMR (CDCl3): 36.7, 38.8, 41.6, 47.1, 49.9, 53.1,
55.5, 66.2, 67.7, 117.5, 127.4, 128.6, 129.9, 133.0, 144.9,
154.1, 154.9, 156.9. IR (KBr): 3440, 2920, 1710, 1670,
.
A solution of allyl(1R,5S,6S)-3-(diphenylphosphor-
yloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-
3-carboxylate (10, 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 9a (0.35 g, 1.0 mmol) 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
/
1.90 (bs, 1H),
/
/
/
/
1510 cmꢂ1
8l: Yield 75.2%. 1H-NMR (CDCl3) dꢃ
6H), 1.92 (m, 1H), 2.27 (m, 1H), 2.63ꢀ2.94 (bs, 3H), 2.95
(m, 2H), 3.50ꢀ3.59 (bs, 4H), 3.86 (bs, 1H), 4.52 (bs, 2H),
5.14ꢀ5.35 (m, 3H), 5.83 (m, 1H), 7.24 (m, 9H), 7.45 (m,
.
chromatography to give 11a (0.43 g, 68.6%) as a yellow
/
1.56ꢀ1.74 (bs,
/
1
amorphous solid. H-NMR (CDCl3) dꢃ
/
1.25 (d, 3H,
6.3 Hz), 1.98 (bs, 1H), 2.46
3.3 and 3.3 Hz), 3.31 (dd, 1H,
/
Jꢃ
(m, 2H), 2.95 (dd, 1H, Jꢃ
Jꢃ
4.19 (m, 3H), 4.55 (d, 2H, Jꢃ
4H), 5.26ꢀ
3230, 1720, 1705, 1660 cmꢂ1
The synthesis of compounds 11bꢀ
/
7.2 Hz), 1.35 (d, 3H, Jꢃ
/
/
/
/
6H). 13C-NMR (CDCl3): 24.6, 27.9, 36.7, 38.8, 41.6,
41.9, 53.1, 55.5, 66.2, 67.7, 117.8, 127.4, 128.5, 129.9,
133.1, 144.9, 154.1, 154.9, 156.5. IR (KBr): 3430, 2930,
/
2.5 and 2.6 Hz), 3.40 (m, 2H), 3.61 (bs, 1H), 4.11ꢀ
/
/
5.4 Hz), 4.72ꢀ
/4.79 (m,
/
5.55 (m, 7H), 5.85 (m, 3H). IR (KBr): 3410,
1710, 1670, 1510 cmꢂ1
8m: Yield 79.5%. 1H-NMR (CDCl3) dꢃ
(bs, 2H), 1.80ꢀ1.1.99 (bs, 3H), 2.27 (m, 1H), 2.63ꢀ
(bs, 2H), 2.95 (m, 2H), 3.21 (bs, 1H), 3.70ꢀ
3.96 (bs, 1H), 4.42 (bs, 2H), 5.14ꢀ5.35 (m, 3H), 5.83 (m,
.
.
/11m were carried
/
1.60ꢀ
/
1.71
2.94
out by the same procedure as described for the
preparation of 11a.
/
/
/3.89 (bs, 4H),
/
3.11. (1R,5S,6S)-6-[(1R)-Hydroxyethyl]-3-[5-(3-
amino-2-hydroxyiminoethyl-1-yl)pyrrolidin-3-yl-thio]-1-
methylcarbapen-2-em-3-carboxylic acid (12a)
1H), 7.24 (m, 9H), 7.45 (m, 6H). 13C-NMR (CDCl3):
28.5, 36.7, 38.8, 41.6, 41.9, 53.1, 55.5, 61.8, 66.2, 67.7,
117.8, 127.4, 128.6, 129.8, 133.0, 144.9, 154.1, 154.9,
156.9. IR (KBr): 3540, 3430, 2930, 1710, 1670, 1500
Compound 11a (0.31 g, 0.50 mmol) and 0.1 g of
Pd(OH)2 (10%) were dissolved in THF/phosphate buffer
cmꢂ1
.

C.-H. Oh et al. / European Journal of Medicinal Chemistry 38 (2003) 751ꢀ
/
758
757
(pH 7) (1:1, 10 mL each). The mixture was hydrogenated
at 50 psi for 1 h. The solution was filtered through celite
for C18H27N5O6S: 441.5031, Found: [Mꢁ
441.3987.
12g: Yield 19.9%. UV lmax: 298 nm. H-NMR (D2O)
dꢃ1.13 (d, 3H, Jꢃ7.3 Hz), 1.20 (d, 3H, Jꢃ6.6 Hz),
1.75 (m, 1H), 2.63 (s, 6H), 2.69ꢀ2.79 (m, 2H), 2.85ꢀ2.96
(m, 2H), 3.28ꢀ3.40 (bs, 2H), 3.55 (bs, 1H), 3.85 (bs, 1H),
/
H]ꢁ
1
and washed with water (2ꢄ/10 mL). The combined
filtrates were washed with ethyl ether (2ꢄ/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 com-
/
/
/
3.93 (bs, 1H), 4.13 (bs, 1H), 4.45 (m, 1H). IR (KBr):
3390, 1755, 1680, 1590, 1420 cmꢂ1. HRMS (FAB) Calc.
pound 12a as an amorphorus solid. Yield 17.9%. UV
for C19H29N5O6S: 455.5297, Found: [Mꢁ
455.3788.
12h: Yield 21.5%. UV lmax: 298 nm. H-NMR (D2O)
dꢃ1.13 (d, 3H, Jꢃ7.2 Hz), 1.20 (d, 3H, Jꢃ6.3 Hz),
1.77 (m, 1H), 2.54ꢀ2.72 (m, 2H), 2.80ꢀ2.92 (m, 2H),
2.99 (t, 2H, Jꢃ5.1 Hz), 3.28ꢀ3.44 (bs, 3H), 3.54 (bs,
1H), 3.70 (t, 2H, Jꢃ5.1 Hz), 3.93 (bs, 1H), 4.16 (bs,
/
H]ꢁ
1
lmax: 298 nm. H-NMR (D2O) dꢃ
/
1.11 (d, 3H, Jꢃ
5.9 Hz), 1.79 (bs, 2H), 2.65 (m,
1H), 2.86 (m, 2H), 3.21ꢀ3.43 (bs, 2H), 3.53 (bs, 1H),
/
6.9
1
Hz), 1.19 (d, 3H, Jꢃ
/
/
/
/
/
3.70 (bs, 1H), 4.10 (m, 2H), 4.51 (bs, 1H). IR (KBr):
3378, 2970, 1745, 1666, 1592, 1392 cmꢂ1. HRMS (FAB)
/
/
/
/
Calc. for C16H24N4O5S: 384.4517, Found: [Mꢁ
384.4557.
The synthesis of compounds 12bꢀ
/
H]ꢁ
/
2H), 4.41 (m, 1H). IR (KBr): 3397, 1756, 1685, 1595,
1401 cmꢂ1. HRMS (FAB) Calc. for C19H29N5O7S:
/
12m were carried
out by the same procedure as described for the
preparation of 12a.
1
12b: Yield 29.2%. UV lmax: 298 nm. H-NMR (D2O)
471.5291, Found: [Mꢁ
12i: Yield 22.2%. UV lmax: 298 nm. H-NMR (D2O)
dꢃ1.10 (d, 3H, Jꢃ7.0 Hz), 1.18 (d, 3H, Jꢃ6.3 Hz),
1.79 (m, 1H), 2.49ꢀ2.67 (m, 3H), 2.92 (m, 1H), 3.08ꢀ
3.16 (bs, 4H), 3.28ꢀ3.43 (bs, 2H), 3.52 (m, 1H), 3.69ꢀ
/
H]ꢁ 471.4555.
1
/
/
/
dꢃ
1.67 (m, 1H), 1.90 (s, 3H), 2.74 (m, 1H), 2.86ꢀ
2H), 3.21ꢀ3.44 (bs, 3H), 3.58 (dd, 1H, Jꢃ
/
1.10 (d, 3H, Jꢃ
/
7.1 Hz), 1.18 (d, 3H, Jꢃ
/
6.3 Hz),
/
/
/
2.96 (m,
/
/
/
/5.4 and 5.8
3.81 (bs, 4H), 3.91 (bs, 1H), 4.05 (bs, 2H), 4.45 (m, 1H).
IR (KBr): 3490, 1740, 1700, 1660, 1400 cmꢂ1. HRMS
Hz), 3.87 (bs, 2H), 4.11 (bs, 2H), 4.43 (m. 1H). IR
(KBr): 3410, 1725, 1686, 1594, 1392 cmꢂ1. HRMS
(FAB) Calc. for C21H31N5O7S: 497.5663, Found: [Mꢁ
H]ꢁ 497.5670.
12j: Yield 20.6%. UV lmax: 298 nm. H-NMR (D2O)
dꢃ1.12 (d, 3H, Jꢃ7.2 Hz), 1.26 (d, 3H, Jꢃ6.4 Hz),
1.88 (m, 1H), 2.45ꢀ2.54 (m, 2H), 2.59 (bs, 4H), 2.90 (m,
1H), 3.15 (bs, 1H), 3.28ꢀ3.44 (bs, 6H), 3.55 (m, 1H),
/
(FAB) Calc. for C18H26N4O6S: 426.4884, Found: [Mꢁ
H]ꢁ 426.4869.
12c: Yield 23.8%. UV lmax: 298 nm. H-NMR (D2O)
dꢃ0.79 (m, 2H), 0.98 (m, 2H), 1.18 (d, 3H, Jꢃ7.1 Hz),
1.31 (d, 3H, Jꢃ6.5 Hz), 1.67 (m, 1H), 1.90ꢀ
2H), 2.63ꢀ2.74 (bs, 3H), 2.96 (m, 1H), 3.21ꢀ
2H), 3.59 (dd, 1H, Jꢃ
/
1
1
/
/
/
/
/
/
/
/
1.99 (bs,
/
/
/
3.44 (bs,
3.75 (bs, 1H), 3.88 (bs, 1H), 4.16 (bs, 2H), 4.45 (m, 1H).
IR (KBr): 3980, 1710, 1660, 1580, 1405 cmꢂ1. HRMS
/5.4 and 5.8 Hz), 3.87 (bs, 1H),
4.11 (bs, 2H), 4.42 (m. 1H). IR (KBr): 3390 (NH), 1745,
1680, 1650, 1410, 1166 cmꢂ1. HRMS (FAB) Calc. for
(FAB) Calc. for C23H31N5O6S2: 513.6329, Found: [Mꢁ
H]ꢁ 513.6341.
12k: Yield 19.2%. UV lmax: 298 nm. m.p. 125ꢀ
(dec.). 1H-NMR (D2O) dꢃ
1.07 (d, 3H, Jꢃ7.0 Hz),
1.14 (d, 3H, Jꢃ6.2 Hz), 1.87 (m, 1H), 2.45ꢀ2.59 (m,
2H), 2.88 (m, 1H), 2.97 (bs, 8H), 3.15 (bs, 1H), 3.28ꢀ
/
C20H28N4O6S: 452.5257, Found: [Mꢁ
/
H]ꢁ 452.5219.
/
136 8C
1
12d: Yield 29.2%. UV lmax: 298nm. H-NMR (D2O)
/
/
dꢃ
/
1.14 (d, 3H, Jꢃ
/
7.2 Hz), 1.25 (d, 3H, Jꢃ/6.6 Hz),
/
/
1.77 (m, 1H), 2.44ꢀ
/
2.57 (m, 2H), 2.96 (m, 1H), 3.21ꢀ
/
/
3.44 (bs, 2H), 3.54 (bs, 1H), 3.83 (bs, 1H), 3.90 (s, 3H),
3.98 (bs, 1H), 4.14 (bs, 2H), 4.43 (m, 1H). IR (KBr):
3400, 1755, 1690, 1639, 1415 cmꢂ1. HRMS (FAB) Calc.
3.44 (bs, 3H), 3.55 (m, 1H), 4.06 (bs, 2H), 4.45 (m. 1H).
IR (KBr): 3470, 1730, 1660, 1586, 1400 cmꢂ1. HRMS
(FAB) Calc. for C31H32N6O6S: 496.5816, Found: [Mꢁ
H]ꢁ 496.5825.
12l: Yield 20.1%. UV lmax: 298 nm. m.p. 114ꢀ
(dec.). 1H-NMR (D2O) dꢃ
1.09 (d, 3H, Jꢃ7.2 Hz),
1.16 (d, 3H, Jꢃ6.4 Hz), 1.58 (bs, 2H), 1.70ꢀ1.88 (m,
4H), 2.01 (m, 1H), 2.45ꢀ2.59 (m, 2H), 2.90 (m, 1H), 3.05
(bs, 4H), 3.55 (m, 1H), 3.75 (bs, 1H), 3.80ꢀ3.88 (bs, 2H),
4.03 (bs, 2H), 4.45 (m, 1H). IR (KBr): 3470, 1730, 1685,
1580, 1425 cmꢂ1
HRMS (FAB) Calc. for
C22H33N5O6S: 495.5935, Found: [Mꢁ
H]ꢁ 495.5921.
12m: Yield 15.9%. UV lmax: 298 nm. 1H-NMR (D2O)
dꢃ1.07 (d, 3H, Jꢃ7.1 Hz), 1.12 (d, 3H, Jꢃ6.2 Hz),
1.52 (bs, 3H), 1.88 (bs, 3H), 2.45ꢀ2.49 (m, 1H), 2.90ꢀ
2.96 (m, 3H), 3.07ꢀ3.19 (bs, 5H), 3.55ꢀ3.67 (m, 2H),
/
for C18H26N4O7S: 442.4878, Found: [Mꢁ
442.4899.
12e: Yield 20.6%. UV lmax: 298 nm. H-NMR (D2O)
dꢃ1.12 (d, 3H, Jꢃ7.2 Hz), 1.25 (d, 3H, Jꢃ6.6 Hz),
1.79 (m, 1H), 2.45ꢀ2.59 (m, 2H), 2.96 (m, 1H), 3.28ꢀ
/
H]ꢁ
/
131 8C
1
/
/
/
/
/
/
/
/
/
/
3.44 (bs, 2H), 3.54 (bs, 1H), 3.88 (bs, 1H), 3.99 (bs, 1H),
4.14 (bs, 2H), 4.45 (m. 1H). IR (KBr): 3388, 1757, 1689,
/
1591, 1409 cmꢂ1
.
HRMS (FAB) Calc. for
H]ꢁ 427.4755.
.
C17H25N5O6S: 427.4765, Found: [Mꢁ
/
/
1
12f: Yield 21.5%. UV lmax: 298 nm. H-NMR (D2O)
dꢃ
1.77 (m, 1H), 2.55 (s, 3H), 2.59ꢀ
(m, 2H), 3.28ꢀ3.44 (bs, 2H), 3.54 (bs, 1H), 3.88 (bs, 1H),
/
1.13 (d, 3H, Jꢃ
/
7.3 Hz), 1.20 (d, 3H, Jꢃ/6.6 Hz),
/
/
/
/
2.75 (m, 2H), 2.80ꢀ
/
2.96
/
/
/
/
/
3.93 (bs, 1H), 4.16 (bs, 1H), 4.45 (m, 1H). IR (KBr):
3397, 1759, 1680, 1591, 1411 cmꢂ1. HRMS (FAB) Calc.
3.88 (bs, 1H), 4.03 (m, 2H), 4.45 (m, 1H). IR (KBr):
3370, 1755, 1690, 1580, 1430 cmꢂ1. HRMS (FAB) Calc.

758
C.-H. Oh et al. / European Journal of Medicinal Chemistry 38 (2003) 751ꢀ758
/
for C22H33N5O7S: 511.5929, Found: [Mꢁ
H]ꢁ
511.5929.
/
[6] G. Bourboulis, P. Grecka, M. Grammatikou, H. Giamarellou,
Abstracts of Papers of 34th Interscience Conference on Anti-
microial Agents Chemotherapy, No. 68, Orlando, FL, 1994.
[7] C.-H. Oh, S.-Y. Hong, K.-H. Nam, J.-H. Cho, Korean J. Med.
Chem. 3 (1993) 82ꢀ
[8] C.-H. Oh, E.-R. Woo, S.-Y. Hong, K.-H. Nam, D.Y. Kim, J.-H.
Cho, Korean J. Med. Chem. 4 (1994) 26ꢀ34.
[9] C.-H. Oh, J.-H. Cho, J. Antibiot. 47 (1994) 126ꢀ
[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.
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/