Synthesis and in-vitro activity of new 1β-methylcarbapenem derivatives as antibacterial agents

Article abstract of DOI:10.1002/ardp.200800014

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 substituents on the pyrrolidine ring was investigated. A particular compound III b having an oxime-pyrrolidine moiety showed the most potent antibacterial activity.

Full text of DOI:10.1002/ardp.200800014

780
Arch. Pharm. Chem. Life Sci. 2008, 341, 780–786
Full Paper
Synthesis and In-Vitro Activity of New 1b-Methylcarbapenem
Derivatives as Antibacterial Agents
Myung-Ho Jung1, Joon Hee Hong2, Jung-Hyuck Cho1, and Chang-Hyun Oh1
1 Biomaterials Research Center, Korea Institute of Science and Technology, Seoul, Korea
2 College of Pharmacy, Chosun University, Kwangju, Korea
The synthesis of a new series of 1b-methylcarbapenems having pyrrolidine and piperidine moi-
eties is described. Their in-vitro antibacterial activities against both Gram-positive and Gram-neg-
ative bacteria were tested and the effect of substituents on the pyrrolidine ring was investigated.
A particular compound III b having an oxime-pyrrolidine moiety showed the most potent anti-
bacterial activity.
Keywords: Antibacterial activity / 1b-Methylcarbapenems / Substituent effects /
Received: January 15, 2008; accepted: May 21, 2008
DOI 10.1002/ardp.200800014
improve the antibacterial activity of the carbapenems is
also discussed.
Introduction
Carbapenems are one of the most potent types of antibac-
terial agents and are among those used as last resort
against infections in the clinical field. Three carbape-
nems, imipenem [1, 2], meropenem [3], and ertapenem
[4] have been marketed so far. It was revealed that 1b-
methylcarbapenems showed not only a broad antibacte-
rial spectrum against both Gram-positive and Gram-nega-
tive bacteria but also high stability to human renal DHP-I
[5; 6]. The carbapenem compounds having a (3S)-pyrroli-
din-3-ylthio group at the C-2 position in the carbapenem
skeleton are noted for their broad and potent antibacte-
rial activity [7], and, therefore, a large number of these
derivatives have been synthesized and investigated [8–
12]. At present, several carbapenem derivatives such as S-
4661 [13], BO-2727 [14], and E-1010 [15] are under clinical
or preclinical studies since the launch of meropenem.
In this paper, we described the synthesis and structure-
activity relationship of the lb-methylcarbapenems hav-
ing a pyrrolidin-3-ylthio moiety at C-2 that is substituted
either with a piperidinylmethyl or a pyrrolidinylmethyl
group at 59 position. Furthermore, our approach to
Results and discussions
Chemistry
Our general synthetic route for the new carbapenems
involved the preparation of appropriately protected thi-
ols containing a pyrrolidine ring as a side chain and a
subsequent coupling reaction with the carbapenem
diphenylphosphates, followed by deprotection of the
resulting protected carbapenems, following a usual
decoupling procedure.
The b-ketoester 3 was prepared in three steps from gly-
cin ester and ethyl acrylate using the Dieckmann conden-
sation method [16]. The intermediate 4 was obtained by
reaction of 3 with 10% hydrochloric acid [17] and was sub-
sequently subjected to hydrogenation in the presence of
palladium carbon to provide the key compound 5
(Scheme 1) [18].
The intermediate 7 was obtained by treatment of the
hydroxy compound 6 [19] with b-keto amine 5 using tri-
fluoromethane sulfonic anhydride. The intermediate 7
was converted to the hydroxy compound 8 by treatment
with sodium borohydride in THF. Preparation of the
oxime 9, and methoxyimino compound 10 was accom-
plished by treatment of compound 7 with hydroxyl-
Correspondence: Chang-Hyun Oh, Biomaterials Research Center, Ko-
rea Institute of Science and Technology, Seoul 130-650, Korea.
E-mail: choh@kist.re.kr
Fax: +82-2-958-5189
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Arch. Pharm. Chem. Life Sci. 2008, 341, 780–786
New 1b-Methylcarbapenem Derivatives
781
Reactions and conditions: (i) Ethyl acrylate, TEA, EtOH; (ii) Benzyl chloroformate, TEA, CH2Cl2; (iii) Potassium t-butoxide, toluene; (iv)
10% HCl; (v) Pd/C, H2, EtOH.
Scheme 1. Synthesis of key compound 5.
Reactions and conditions: (i) 1.) Trifluoromethane sulfonic anhydride, CH2Cl2, 2.) 5, TEA, CH2Cl2; (ii) NaBH4, THF; (iii) Trifluoroacetic
acid, triethylsilane, CH2Cl2; (iv) Hydroxylamine, EtOH; (v) Methoxylamine hydrochloride, pyridine.
Scheme 2. Synthesis of the mercaptans Ia–d.
Reactions and conditions: (i) DAST, CH2Cl2; (ii) Trifluoroacetic acid, triethylsilane, CH2Cl2.
Scheme 3. Synthesis of mercaptan Ie.
amine and methoxylamine, respectively. Deprotection of
Compounds 15 and 16 were prepared by a similar man-
the trityl group to mercaptans Ia–d was achieved by ner to that described for the preparation of 5 (Scheme 4).
treatment of 7–10 with trifluoroacetic acid in the pres-
ence of triethylsilane (Scheme 2).
The treatment of the hydroxy compound 6 with the
piperidine derivative 16 using trifluoromethane sulfonic
Preparation of the fluoro compound 11 was accom- anhydride gave the intermediate 17, which was success-
plished by treatment of the hydroxyl compound 8 with fully converted into derivatives 18–20, using the same
DAST (diethylaminosulfur trifluorid).
procedure described for the preparation of compounds
The reaction of benzylamine with excess of ethylacry- 7–10 (Scheme 5).
late in the presence of triethylamine gave 13, through a
Finally, the reaction of 21 with the thiols (Ia–i) in the
bis-addition, in excellent yield. Compound 13 was sub- presence of diisopropylethylamine gave the correspond-
jected to Dieckmann cyclization with sodium hydride to ing 2-substituted carbapenems (IIa–i). Deprotection of
give ethyl-N-benzyl-4-oxo-piperidinecarboxylate 14 in these compounds by treatment with tetrakis(triphenyl-
moderate yield [20].
phosphine)palladium(0) and tributyltin hydride gave the
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M.-H. Jung et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 780–786
Reactions and conditions: (i) Ethyl acrylate, TEA, EtOH; (ii) NaH, toluene; (iii) 10% HCl; (iv) Pd/C, H2, EtOH.
Scheme 4. Synthesis of key compound 16.
Reactions and conditions: (i) 1.) Trifluoromethane sulfonic anhydride, CH2Cl2, 2.) 16, TEA, CH2Cl2; (ii) NaBH4, THF; (iii) Tri-
fluoroacetic acid, triethylsilan, CH2Cl2; (iv) Hydroxylamine, EtOH; (v) Methoxylamine hydrochloride, pyridine.
Scheme 5. Synthesis of mercaptans If–Ii.
Reactions and conditions: (i) N,N'-Diisopropylethyl amine, Ia–e; (ii) Tetrakis(triphenylphosphine)palladium, tributyltin hydride, CH2Cl2.
Scheme 6. Synthesis of the carbapenems IIIa–e.
crude products, which were purified on a HP-20 column tosoy broth was diluted to about 106 cells/mL with the
to give the pure carbapenems (IIIa–i) (Schemes 6 and 7).
same broth and inoculated with an inoculating device
onto agar-containing serial twofold dilutions of the test
compounds. Organisms were incubated at 378C for 18–
Biological studies
The MICs were determined by the agar dilution method 20 hours. The MIC of a compound was defined as the low-
using test agar. An overnight-culture of bacteria in tryp- est concentration that visibly inhibited growth.
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Arch. Pharm. Chem. Life Sci. 2008, 341, 780–786
New 1b-Methylcarbapenem Derivatives
783
Reactions and conditions: (i) N,N 9-Diisopropylethyl amine, If–i; (ii) Tetrakis(triphenylphosphine)palladium, tributyltin hydride, CH2Cl2.
Scheme 7. Synthesis of the carbapenems IIIf–i.
Table 1. In-vitro antibacterial activity (MIC, in lg/mL) of the carbapenem derivatives.
STRAINS
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
IIIi
IPMa)
1.56
0.025
1.56
Staphylococcus aureus 1218
Coagulase negative staphylococci
Enterococcus faecalis 2347
Streptococcus pyogenes 9889
Streptococcus agalaciae 32
Streptococcus pneumoniae 0025
Haemophilus influenzae 1210
Escherichia coil 04
Klebsiella peneumoniae 523
Citrobacter freundii 323
Enterobactor cloacae 34
Serratia marcescens 3349
Acinetobacter baumannii 2289
Psudemonas aeruginosa 5455
6.25
0.391 0.098
6.25 1.563
0.098 0.013
0.049 0.025
0.098 0.013
3.12
3.12
0.098
3.12
6.25
0.391
6.25
3.12
0.195
6.25
3.12
0.391
12.5
0.098
0.098
0.098
6.25
0.391
0.781
0.391
0.781
0.781
25
6.25
0.195
12.5
0.049
0.049
0.025
6.25
0.098
0.195
0.098
0.391
0.391
12.5
0.391
12.5
0.049 a0.01
0.049 0.01
0.781
25
0.198
0.098
0.098
0.025
0.025
0.025
3.12
0.098
0.098
0.098
0.098
0.098
6.25
0.098
0.098
0.098
6.25
0.195
0.195
0.195
0.195
0.391
0.049
0.049
0.025
6.25
0.195
0.391
0.195
0.195
0.391
0.025 a0.01
12.5
6.25
3.12
12.5
6.25
0.098 0.025
0.098 0.049
0.098 0.025
0.098 0.049
0.195 0.098
0.391
0.781
0.391
1.563
1.563
0.195
0.391
0.195
0.391
0.781
0.391
0.781
0.391
0.781
0.781
12.5
12.5
3.12
3.12
12.5
6.25
25
6.25
50
50
25
50
12.5
12.5
12.5
50
12.5
3.12
6.25
a)
Imipenem.
We would like to thank Hawon Pharmaceuticals Co. which supported
us with funding and also thank Mrs Seo Sun Hee in KIST forthe anti-
bacterial tests.
The in-vitro antibacterial activities of the new carbape-
nems (IIIa–i) prepared above against Gram-positive and
negative bacteria are listed in Table 1. For comparison,
the MIC values of imipenem are also listed. All com-
pounds displayed superior or similar antibacterial activ-
ities against Gram-negative bacteria to imipenem. In par-
ticular, against Escherichia coli, most of the compounds
showed higher activity when compared to imipenem. By
comparing the activity of derivatives substituted with
pyrrolidine and piperidine moieties at C-5 of the pyrroli-
dine side chain, it was found that the derivatives with
pyrrolidine moieties IIIa–e were generally more potent
than the derivatives with piperidine moieties IIIf–i. The
effects of substituents on the pyrrolidine and piperidine
ring were also investigated. Compounds IIIb and IIIg hav-
ing the oxime and fluoro group were generally more
potent than those with hydroxy or methoxy imine
groups. As a result, among all of these derivatives, com-
pound IIIb having an oxime-pyrrolidine moiety showed
the most potent antibacterial activity.
The authors have declared no conflict of interest.
Experimental
UV spectra: Hewlett Packard 8451A UV-VIS spectrophotometer
(Hewlett Packard, Palo Alto, CA, USA). – IR spectra: Perkin Elmer
16F-PC FT-IR (Perkin-Elmer, Norwalk, CT, USA). – NMR spectra:
Varian Gemini 300 spectrometer (Varian Inc., Palo Alto, CA,
USA), tetramethylsilane (TMS) as an internal standard. The mass
spectrometry system was based on a HP5989A MS Engine mass
spectrometer with a HP Model 59987A (both, Hewlett Packard).
Chemistry
(2S,4S)-2-[(4-oxopyrrolidinyl)methyl]-4-tritylthio-1-
(allyloxycarbonyl)pyrrolidine 7
To a solution of 6 (1.5 g, 3.3 mmol) in dry CH2Cl2 (10 mL), trie-
thylamine (0.9 mL, 6.6 mmol) and trifluoromethane sulfonic
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Arch. Pharm. Chem. Life Sci. 2008, 341, 780–786
anhydride (0.66 mL, 4.0 mmol) were added dropwise and the sol-
ution was stirred for 45 min at –708C. An ice-cooled solution of
5 (1.2 g, 9.9 mmol) and triethylamine (2.3 mL, 24.2 mmol) in dry
CH2Cl2 was slowly added to the above solution at –708C and the
mixture was stirred for 2 h 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 chromatogra-
phy (EtOAc / hexane = 1 : 1) to give 7 (0.85 g, 49%). 1H-NMR
(CDCl3) d: 1.66–1.72 (m, 2H), 2.08–2.16 (m, 2H), 2.47–2.54 (m,
2H), 2.65–2.84 (m, 6H), 2.98 (q, J = 6.9 Hz, 1H), 3.66–6.68 (bs, 1H),
4.37–4.43 (m, 2H), 5.12–5.18 (bs, 2H), 5.73–5.79 (m, 1H), 7.20–
7.33 (m, 9H), 7.37 (m, 6H). 13C-NMR (300 MHz; CDCl3) d: 8.6, 14.6,
29.6, 36.9, 37.8, 41.4, 45.7, 52.2, 52.5, 55.7, 59.0, 65.6, 67.3, 117.2,
126.8, 128.0, 129.5, 132.8, 144.6, 144.7, 154.3, 214.4.
10% NaHCO3, and brine, respectively. The organic layer was con-
centrated in vacuo to give a residue, which was purified by silica
gel column chromatograph (EtOAc / hexane = 1 : 2) to give 10
(0.7 g, 60%). 1H-NMR (CDCl3) d: 1.25–1.33 (m, 1H), 1.74–1.84 (m,
1H), 2.18–2.22 (bs, 1H), 2.51–2.59 (m, 3H), 2.60–2.91 (m, 6H),
3.27 (m, 2H,), 3.88 (m, 3H), 4.40–4.60 (bs, 2H), 5.19–5.29 (m, 2H),
5.81–5.92 (m, 1H), 7.21–7.33 (m, 9H), 7.47 (d, J = 7.5 Hz, 6H). 13C-
NMR (300 MHz CDCl3) d: 14.2, 27.2, 29.6, 37.2, 41.4, 54.2, 55.9,
56.4, 58.8, 59.6, 61.5, 65.5, 67.3, 117.1, 126.8, 127.8, 128.0, 129.5,
130.1, 132.8, 144.7, 154.2, 161.8.
(2S,4S)-2-[(4-Fluoropyrrolidinyl)methyl]-4-tritylthio-1-
(allyloxycarbonyl)pyrrolidine 11
To a suspension of compound 8 (0.9 g, 1.7 mmol) in dry CH2Cl2
was added diethylamine sulfur trifluoride (0.4 mL, 2.7 mmol) at
–708C, the mixture was stirred at –708C for 45 min and then
allowed to warm to room temperature. At this time, 4 mL of
methanol were added to quench the reaction. The solvent was
evaporated in vacuo and the resulting oil dissolved in ethyl ace-
tate, neutralized (pH = 7–8) by addition of 32% ammonia solu-
tion, and extracted with ethyl acetate. The organic phase was
washed with brine, dried over MgSO4, and then evaporated. The
crude residue was purified by silica gel column chromatography
(EtOAc / hexane = 1 : 2) to give 11 (0.4 g, 48%). 1H-NMR (CDCl3) d:
1.12–1.33 (m, 3H), 1.78–1.90 (m, 1H), 2.00–2.10 (m, 2H), 2.44–
2.56 (m, 2H), 2.65–2.81 (m, 6H), 3.68–3.80 (bs, 1H), 4.30–4.50
(bs, 2H), 5.18–5.31 (m, 2H), 5.82–5.88 (m, 1H), 7.09–7.21 (m, 9H),
7.46 (d, J = 6.9 Hz, 6H). 13C-NMR (300 MHz, CDCl3) d: 32.6, 32.9,
41.0, 52.7, 65.5, 67.3, 76.5, 92.2, 94.5, 126.8, 128.0, 129.5, 132.9,
144.7, 154.2.
(2S,4S)-2-[(4-Hydroxypyrrolidinyl)methyl]-4-tritylthio-1-
(allyloxycarbonyl)pyrrolidine 8
To a solution of 7 (1.3 g, 2.5 mmol) in THF (30 mL), NaBH4 (0.2 g,
4.9 mmol) was added slowly at 08C and the resulted mixture was
stirred for 2 h at room temperature. The reaction mixture was
poured into ice water, acidified to pH = 4–5 with acetic acid, and
then extracted with ethyl acetate. Evaporation of the solvent in
vacuo gave a crude residue, which was purified by silica gel col-
umn chromatography (EtOAc / Hexane; 1 : 2) to give 8 (0.9 g,
1
71%) as a pale yellow oil. H-NMR (CDCl3) d: 1.67–1.76 (m, 2H),
2.05–2.10 (m, 4H), 2.46–2.05 (m, 2H), 2.53–3.24 (m, 6H), 3.77
(bs, 1H), 4.17–4.26 (s, 1H), 4.47 (bs, 2H), 5.12–5.31 (m, 2H), 5.83–
5.89 (m, 1H), 7.21–7.33 (m, 9H), 7.46 (d, J = 6.8 Hz, 6H). 13C-NMR
(300 MHz, CDCl3) d: 14.2, 34.8, 37.2, 41.0, 41.5, 52.5, 55.9, 58.6,
59.4, 63.4, 65.5, 67.3, 71.4, 117.1, 126.8, 127.0, 128.0, 128.4,
129.2, 129.5, 129.8, 130.1, 132.9, 144.7, 154.3.
(2S,4S)-2-[(4-Hydroxyiminopyrrolidinyl)methyl]-4-
tritylthio-1-(allyloxycarbonyl) pyrrolidine 9
Preparation of compounds 17–20
Compounds 17, 18, 19 and 20 were prepared from 6, as described
for the preparation of 7, 8, 9 and 10, respectively.
To a stirred solution of 7 (1.3 g, 2.4 mmol) in EtOH (20 mL),
hydroxylamine hydrochloride (0.1 g, 8.3 mmol) and triethyl-
amine (1.1 mL, 8.3 mmol) was added dropwise, and the resulted
mixture was stirred for 7 h at 608C. The reaction mixture was
diluted with ethyl acetate (30 mL) and water (50 mL), and then
the organic layer was dried over anhydrous Na2SO4. The solvent
was removed in vacuo, and purification by flash chromatography
(EtOAc / hexane; 1 : 2) afforded 9 (0.91 g, 70%). 1H-NMR (CDCl3) d:
1.66–1.80 (m, 1H), 2.12–2.34 (m, 2H), 2.50–2.63 (m, 3H), 2.76–
2.92 (m, 6H), 3.23–3.30 (bs, 1H), 3.41–3.46 (bs, 1H), 3.72–3.83
(bs, 1H), 4.40–4.62 (bs, 2H), 5.22–5.28 (m, 2H), 5.87–5.89 (m,
1H), 7.21–7.33 (m, 9H), 7.47 (d, J = 7.1 Hz, 6H). 13C NMR (300 MHz,
CDCl3) d: 14.1, 22.7, 26.8, 29.3, 29.6, 30.0, 37.1, 52.5, 55.8, 56.3,
65.6, 67.3, 117.1, 126.8, 127.0, 128.0, 128.3, 129.2, 129.5, 129.9,
132.8, 144.3, 144.7, 145.1, 151.8, 154.3, 162.5.
1
17: H-NMR (CDCl3) d: 0.82–0.90 (m, 2H), 1.32–1.44 (m, 1H),
1.76–1.84 (m, 2H), 2.71–2.83 (m, 7H), 2.90–2.99 (m, 2H), 3.16–
3.23 (m, 1H), 3.63–3.85 (bs, 1H), 4.33–4.51 (m, 2H), 5.17–5.22
(bs, 2H), 5.81–5.92 (m, 1H), 7.21–7.31 (m, 9H), 7.43–7.47 (m, 6H).
13C-NMR (300 MHz, CDCl3) d: 11.4, 14.2, 21.0, 22.6, 29.0, 31.5,
38.4, 41.3, 43.7, 52.1, 53.5, 55.5, 58.7, 59.5, 60.3, 65.5, 67.1, 67.4,
67.5, 117.1, 126.9, 127.1, 128.3, 129.2, 129.4, 132.8, 144.4, 144.6,
144.8, 154.2, 160.8, 171.0, 209.1.
1
18: H-NMR (CDCl3) d: 1.65–1.83 (m, 6H), 2.42–2.61 (m, 4H),
2.66–2.82 (m, 3H), 3.14–3.17 (m, 4H), 3.62–3.76 (m, 1H), 4.46–
4.51 (m, 2H), 5.18–5.31 (m, 2H), 5.80–5.93 (m, 1H), 7.22–7.32
(m, 9H), 7.45-7.48 (m, 6H). 13C-NMR (300 MHz, CDCl3) d: 14.5, 21.0,
29.7, 32.5, 33.4, 37.3, 38.4, 41.6, 43.7, 47.4, 51.0, 52.1, 52.5, 55.3,
58.7, 60.4, 65.53, 66.9, 67.1, 67.3, 76.6, 98.4, 117.0, 126.8, 126.9,
128.0, 129.4, 129.5, 130.1, 132.9, 144.4, 144.6, 154.2.
1
19: H-NMR (CDCl3) d: 1.24–1.29 (m, 1H), 1.70–1.79 (m, 1H),
(2S,4S)-2-[(4-Methoxyiminopyrrolidinyl)methyl]-4-
tritylthio-1-(allyloxycarbonyl)pyrrolidine 10
To a solution of 7 (1.1 g, 2.1 mmol) in dry pyridine (20 mL),
methoxylamine hydrochloride (0.6 mL, 3.2 mmol, 35%) was
added dropwise, and the resulted mixture was stirred for 10 h at
508C. The mixture was evaporated under reduced pressure. The
residue was dissolved in ethyl acetate and washed with 1 N HCl,
2.31–2.39 (m, 4H), 2.51–2.61 (m, 6H), 2.75–2.80 (m, 3H), 3.21–
3.26 (bs, 1H), 3.75–3.81 (bs, 1H), 4.47–4.53 (m, 2H), 5.21–5.26
(m, 2H), 5.80–5.93 (m, 1H), 7.20–7.33 (m, 9H), 7.45–7.48 (m, 6H).
1
20: H-NMR (CDCl3) d: 0.84–0.91 (m, 2H), 1.27–1.32 (m, 2H),
2.29–2.31 (m, 3H), 2.52–2.57 (m, 6H), 2.82–2.91 (m, 3H), 3.82–
3.86 (s, 3H), 4.12–4.17 (m, 2H), 5.21–5.31 (m, 2H), 5.72–5.91 (m,
1H), 7.20–7.33 (m, 9H), 7.45–7.47 (m, 6H).
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Arch. Pharm. Chem. Life Sci. 2008, 341, 780–786
New 1b-Methylcarbapenem Derivatives
785
(m, 3H), 3.54–3.63 (m, 2H), 4.07–4.22 (m, 3H), 4.60–4.66 (m, 3H),
4.66-4.68 (dd, J = 5.5 Hz, 1H), 4.86–4.88 (dd, J = 5.4 Hz, 1H), 5.29–
5.35 (m, 3H), 5.92–6.03 (m, 2H).
Allyl (1R,5S,6S)-6-[(1R)-hydroxyethyl]-2-[[5-(4-
hydroxypyrrolidinyl)methyl]-1-(allyloxycarbonyl)pyrrolidin-
3-ylthio]-1-methylcarbapen-2-em-3-carboxylate IIa
IIh: Yield 19%. 1H-NMR (CDCl3) d: 1.26–1.36 (d, J = 6.1 Hz, 3H),
1.36–1.38 (m, 2H), 2.08–210 (m, 1H), 2.13–2.15 (m, 1H), 2.31–
2.37 (m, 2H), 2.41–2.57 (m, 8H), 2.59–2.71 (m, 2H), 3.37–3.53
(m, 3H), 3.82–3.84 (s, 3H), 4.05–4.19 (m, 3H), 4.22–4.27 (m, 2H),
4.59–4.66 (m, 3H), 4.68–4.72 (dd, J = 5.5 Hz, 1H), 4.81–4.85 (dd, J
= 5.3 Hz, 1H), 5.21–5.34 (m, 3H), 5.89–6.02 (m, 2H).
To a solution of 8 (0.6 g, 1.2 mmol) in CH2Cl2 (3 mL) was added
dropwise triethylsilane (0.2 mL, 1.2 mmol) at 58C, and then TFA
(1.2 mL). After stirring for 30 min at room temperature, the mix-
ture was evaporated under reduced pressure. The residue was
dissolved in ethyl acetate and washed with 10% NaHCO3, brine.
The organic layer was concentrated in vacuo to give a residue Ia,
which was used without further purification. A solution of allyl
(1S,5S,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-hydroxyethyl]-1-
methylcarbapen-2-em-3-carboxylate 21 (0.6 g, 1.2 mmol) in
CH3CN (10 mL) was cooled to 08C under N2. To this solution was
added diisopropylethyl amine (0.13 g, 1.0 mmol) and a solution
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. Evapora-
tion in vacuo gave a foam, which was purified by silica gel chro-
matography (EtOAc / MeOH = 10 : 1) to give IIa (99.0 mg, 21%). 1H-
NMR (CDCl3) d: 0.83–0.94 (m, 3H), 0.95–1.24 (m, 4H), 1.60–1.76
(m, 3H), 2.02–2.17 (m, 2H), 2.18–2.32 (m, 2H), 2.35–2.53 (m, 2H),
2.80–2.93 (m, 3H), 3.21–3.38 (m, 2H), 3.45–3.55 (m, 1H), 3.75–
3.89 (m, 1H), 3.89–4.09 (m, 3H), 4.32–4.57 (bs, 3H), 4.70–4.74
(dd, J = 5.5 Hz, 1H) 4.74–4.78 (dd, J = 5.7 Hz, 1H), 5.20–5.30 (m,
2H), 5.41 (s, 1H), 5.47 (s, 1H), 5.89–5.99 (m, 2H).
IIi: Yield 22%.1H-NMR(CDCl3) d: 1.17–1.18 (m, 2H), 1.30–1.39
(m, 2H), 1.57–1.68 (bs, 2H), 1.69–1.71 (m, 2H) 2.03–2.07 (m, 1H),
2.21–2.22 (m, 1H), 2.35–2.54 (m, 3H), 3.27–3.45 (m, 3H), 3.65–
3.79 (m, 3H), 3.99–4.17 (m, 4H), 4.19–4.27 (m, 2H), 4.61–4.63
(m, 4H), 4.71–4.75 (dd, J = 5.7 Hz, 1H), 4.81–4.85 (dd, J = 5.5 Hz,
1H), 5.24–5.31 (m, 3H), 5.43–5.45 (bs, 1H), 5.91–6.02 (m, 2H).
(1R,5S,6S)-6-[(1R)-Hydroxyethyl]-2-[[5-(4-
hydroxypyrrolidinyl)methyl]pyrrolidin-3-ylthio]-1-
methylcarbapen-2-em-3-carboxylic acid IIIa
To a stirred solution of IIa (40 mg, 0.1 mmol) and Pd(PPh3)4
(30 mg) in CH2Cl2 (10 mL) was added dropwise n-tributytin
hydride (0.1 mL, 0.15 mmol) at 08C and was stirred for 1 h at
same temperature. To the resulting solution was diluted with
water (10 mL) and organic layers was washed with water
(2610 mL). The combined aqueous layers were washed with
ethyl ether (2610 mL) and lyophilized to give a yellow power
which was purified on a Diaion HP-20 column, eluting with 2%
Synthesis of compounds IIb–i
The synthesis of compounds IIb–i was carried out by the same
procedure as described for the preparation of IIa.
1
THF in water. IIIa as an amorphous solid. Yield (24%). H-NMR
(D2O) d: 1.10–1.13 (d, J = 7.0 Hz, 3H), 1.19–1.22 (d, J = 6.2 Hz, 3H),
1.56–1.66 (m, 2H), 1.79–1.81 (m, 1H), 1.87–1.92 (m, 1H), 1.93–
1.98 (m, 2H), 2.21–2.37 (m, 1H), 2.38–2.70 (m, 3H), 2.82–2.91
(m, 3H), 3.02–3.05 (m, 1H), 3.06–3.15 (m, 1H), 3.21–3.25 (m, 5H),
3.59–3.63 (m, 2H), 3.65–3.79 (m, 1H). -IR (KBr): 3470, 1710, 1650
cm– 1. –HRMS (FAB) Calcd. for C19H29N3O5S: 411.1828. Found:
411.1827.
IIb: Yield 32%. 1H-NMR (CDCl3) d: 1.25 (m, 3H), 1.35 (d, J =
6.2 Hz, 3H), 1.50–1.62 (s, 4H), 2.47–2.53 (m, 2H), 2.63–2.82 (m,
6H), 3.18–3.49 (m, 2H), 3.57–3.59 (m, 2H), 4.00–4.17 (m, 1H),
4.18–4.30 (m, 2H), 4.52–4.62 (m, 3H), 4.65–4.73 (dd, J = 5.4 Hz,
1H), 4.80–4.88 (dd, J = 5.5 Hz, 1H), 5.20–5.30 (m, 2H), 5.42 (m,
1H), 5.47 (d, J = 1.5 Hz, 1H), 5.92–5.99 (m, 2H).
1
IIc: Yield 27%. H-NMR (CDCl3) d: 1.25 (m, 3H), 1.34 (d, J =
6.2 Hz, 3H), 1.53–1.65 (s, 4H), 2.53–2.55 (m, 2H), 2.70–2.94 (m,
6H), 3.25–3.47 (m, 2H), 3.56–3.61 (m, 1H), 3.84–3.85 (s, 3H),
4.00–4.15 (m, 2H), 4.21–4.24 (m, 1H), 4.52–4.64 (m, 3H), 4.66–
4.72 (dd, J = 5.4 Hz, 1H), 4.80–4.82 (dd, J = 5.5 Hz, 1H), 5.21–5.48
(m, 4H), 5.89–6.00 (m, 2H).
Synthesis of compounds IIIb–i
The synthesis of compounds IIIb–i was carried out by the same
procedure as described for the preparation of IIIa.
IIIb: Yield 22%. UV kmax: 298 nm. 1H-NMR (CDCl3) d: 1.25 (m,
3H), 1.35 (d, J = 6.2 Hz, 3H), 1.50–1.62 (s, 4H), 2.47–2.53 (m, 2H),
2.63–2.82 (m, 6H), 3.18–3.49 (m, 2H), 3.57–3.59 (m, 2H), 4.00–
4.17 (m, 1H), 4.18–4.30 (m, 2H), 4.52–4.62 (m, 3H), 4.65–4.73
(dd, J = 5.4 Hz, 1H), 4.80–4.88 (dd, J =5.5 Hz, 1H), 5.20–5.30 (m,
2H), 5.42 (m, 1H), 5.47 (d, J =1.5 Hz, 1H), 5.92–5.99 (m, 2H). -IR
(KBr): 3450, 1740, 1670 cm– 1.–HRMS (FAB) Calcd. for
C19H28N4O5S: 424.1780. Found: 424.1760.
IId: Yield 24%. 1H-NMR(CDCl3) d: 1.26 (m, 3H), 1.35 (d, J =
9.4 Hz, 3H), 1.58–1.68 (bs, 2H), 1.99–2.12 (m, 1H), 2.38 (t, J =
6.9 Hz, 3H), 2.83–3.02 (m, 6H), 3.23–3.20 (m, 1H), 3.32–3.47 (m,
2H), 3.98–4.20 (m, 3H), 4.58–4.60 (m, 2H), 4.59-4.60 (dd, J =
5.4 Hz, 1H), 4.81–4.82 (dd, J = 5.5 Hz, 1H), 5.21–5.35 (m, 2H), 5.47
(s, 1H), 5.48 (s, 1H), 5.92–6.02 (m, 2H).
IIe: Yield 21%. 1H-NMR (CDCl3) d: 1.25 (m, 3H), 1.34 (d, J =
6.2 Hz, 3H), 1.56–1.58 (s, 3H), 1.99–2.15 (m, 3H), 2.66–2.84 (m,
6H), 3.22–3.26 (m, 1H), 3.30–3.40 (m, 2H), 3.44 (t, J = 6.9 Hz, 1H),
3.97–4.08 (m, 2H), 4.13–4.28 (m, 1H), 4.50–4.58 (m, 3H), 4.60–
4.71 (dd, J = 5.5 Hz, 1H), 4.72–4.83 (dd, J = 5.6 Hz, 1H), 5.20–5.48
(m, 4H), 5.89-5.99 (m, 2H).
IIIc : Yield 24%. UV kmax: 298 nm. 1H-NMR(CDCl3) d: 1.25 (m,
3H), 1.34 (d, J = 6.2 Hz, 3H), 1.53–1.65 (s, 4H), 2.53–2.55 (m, 2H),
2.70–2.94 (m, 6H), 3.25–3.47 (m, 2H), 3.56–3.61 (m, 1H), 3.84–
3.85 (s, 3H), 4.00–4.15 (m, 2H), 4.21–4.24 (m, 1H), 4.52–4.64 (m,
3H), 4.66–4.72 (dd, J = 5.4 Hz, 1H), 4.80–4.82 (dd, J = 5.5 Hz, 1H),
5.21–5.48 (m, 4H), 5.89–6.00 (m, 2H).–IR (KBr): 3470, 1710, 1680
cm– 1. –HRMS (FAB) Calcd. for C20H30N4O5S: 438.1937. Found:
438.1937.
IIf: Yield 20%. 1H-NMR (CDCl3) d: 1.20–1.35 (m. 3H), 2.03–2.18
(m, 3H), 2.37–2.51 (m, 9H), 2.67–2.87 (m, 6H), 3.26–3.50 (m, 4H),
3.90–4.17 (m, 3H), 4.58–4.62 (m, 3H), 4.66–4.71 (dd, J =5.7 Hz,
1H), 4.81–4.86 (dd, J = 5.5 Hz, 1H), 5.21–5.36 (m, 4H), 5.87-6.00
(m, 2H).
IIId: Yield 18%. UV kmax: 298 nm. 1H-NMR (D2O) d: 1.08–1.12
(d, J = 7.1 Hz, 3H), 1.13–1.17 (d, J = 6.3 Hz, 3H), 1.48–1.63 (m, 1H),
2.34–2.36 (m, 3H), 2.48–2.60 (m, 1H), 2.60–2.64 (m, 1H), 2.65–
3.79 (m, 2H), 2.80–3.08 (m, 2H), 3.24–3.33 (m, 4H), 3.34–3.36
(m, 2H), 3.60–3.79 (m, 2H), 3.81–3.93 (m, 1H), 4.09–4.13 (m, 2H).
IIg: Yield 23%.1H-NMR (CDCl3) d: 1.24–1.27 (d, J = 9.0 Hz, 3H),
1.36–1.38 (m, 2H), 2.04–2.07 (m, 1H), 2.09–2.11 (m, 1H), 2.32–
2.40 (m, 2H), 2.42–2.49 (m, 2H), 2.54–2.80 (m, 9H), 3.25–3.47
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

786
M.-H. Jung et al.
Arch. Pharm. Chem. Life Sci. 2008, 341, 780–786
-IR (KBr): 3460, 1740, 1710, 1670 cm– 1. –HRMS (FAB) Calcd. for
C19H27N3O5S: 409.1671. Found: 409.1670.
[2] J. Birnbaum, F. M. Kahan, J. S. MacDonald, Am. J. Med.
1985, 78, (Suppl. 6A), 3–21.
IIIe: Yield 26%. UV kmax: 298 nm. 1H-NMR (D2O) d: 1.09–1.11
(d, J = 7.1 Hz, 3H), 1.16–1.18 (d, J = 6.3 Hz, 3H), 1.92–2.10 (m, 3H),
2.46–2.51 (m, 3H), 2.60–2.88 (m, 6H), 2.95–3.21 (m, 2H), 3.33–
3.40 (m, 2H), 3.55–3.62 (m, 2H), 3.80–3.98 (m, 2H), 4.11–4.13
(m, 2H). -IR (KBr): 3460, 1710, 1650 cm– 1. –HRMS (FAB) Calcd. for
C19H28FN3O4S: 413.1785. Found: 413.1780.
[3] M. Sunagawa, H. Matsumure, T. Inoue, M. Kato, J. Antibiot.
1990, 43, 519–532.
[4] C. J. Gill, J. J. Jackson, L. S. Gerckens, B. A. Pelak, et al., Anti-
microb. Agents Chemother. 1998, 42, 1996–2001.
[5] D. H. Shih, F. L. Baker, B. G. Christensen, Heterocycles 1984,
21, 29–40.
IIIf: Yield 24%. UV kmax: 298 nm.1H-NMR(D2O) d: 1.02–1.09 (d,
J = 6.0 Hz, 3H), 1.11–1.18 (d, J = 7.0 Hz, 3H), 2.42–2.46 (m, 6H),
2.57–2.62 (m, 4H), 2.73–2.81 (m, 3H), 3.06–3.12 (m, 3H) 3.23–
3.32 (m, 3H), 3.36–3.68 (m, 3H), 4.05–4.08 (m, 3H). -IR (KBr):
3460, 1710, 1650 cm– 1. -HRMS (FAB) Calcd. for C20H31N3O5S:
425.1984. Found: 425.1981.
[6] D. H. Shih, F. L. Baker, B. G. Christensen, Tetrahedron Lett.
1985, 26, 587–590.
[7] M. Sato, M. Takemura, S. Atarashi, K. Higashi, et al., J. Anti-
biot. 1987, 40, 1292–1302.
[8] C.-H. Oh, J.-H. Cho, J. Antibiot. 1994, 47, 126–128.
IIIg: Yield 19%. UV kmax: 298 nm. 1H-NMR (D2O) d: 1.13–1.15
(d, J = 6.2 Hz, 3H), 1.16–1.18 (d, J = 7.1 Hz, 3H), 1.51–1.72 (m, 3H),
2.42–2.53 (m, 3H), 2.53–2.76 (m, 9H), 3.07–3.15 (m, 1H), 3.17–
3.21 (m, 2H), 3.24–3.30 (m, 3H), 3.51–5.72 (m, 3H). -IR (KBr):
3460, 1710, 1650 cm– 1. -HRMS (FAB) Calcd. for C20H30N4O5S:
438.1937. Found: 438.1934.
[9] C. B. Jin, I. S. Jung, H.-J. Ku, J. W. Yook, et al., Toxicology
1999, 138, 59–67.
[10] C.-H. Oh, H.-W. Cho, I.-K. Lee, J.-Y. Gong, et al., Arch. Pharm.
Pharm. Med. Chem. 2002, 335, 152–158.
[11] C.-H. Oh, H.-G. Dong, H.-W. Cho, S. J. Park, et al., Arch.
Pharm. Pharm. Med. Chem. 2002, 335, 200–206.
1
IIIh: Yield 24%. UV kmax: 298 nm. H-NMR(D2O) d: 1.06–1.08
(d, J = 6.2 Hz, 3H), 1.24–1.26 (d, J = 7.1 Hz, 3H), 1.41–1.58 (m, 2H),
2.22–2.24 (m, 2H), 2.35–2.55 (m, 5H), 2.57–2.73 (m, 6H), 3.10–
3.15 (m, 1H), 3.16–3.21 (m, 1H), 3.30–3.32 (m, 1H), 3.37–3.44
(m, 2H), 3.64–3.68 (s, 3H), 3.78–3.82 (m, 1H), 4.09–4.17 (m, 2H). -
[12] C.-H. Oh, H.-W. Cho, J.-H. Cho, Eur. J. Med. Chem. 2002, 37,
743754.
[13] Y. Iso, T. Irie, Y. Nishino, K. Motokawa, Y. Nishitani, J. Anti-
biot. 1996, 49, 199–209.
IR (KBr): 3460, 1710, 1650 cm– 1
. –HRMS (FAB) Calcd. for
[14] K. Inoue, Y. Hamana, T. Inoue, M. Fukasawa, M. Kato,
Abstracts of Papers of 34th Intersci. Conf. on Antimicrob.
Agents Chemother., No. 1, Orlando, 1994.
C21H32N4O5S: 452.2093. Found: 452.2091.
IIIi: Yield 34%. UV kmax: 298 nm.1H-NMR(D2O) d: 1.04–1.10 (d,
J = 6.3 Hz, 3H), 1.21–1.25 (d, J = 7.1 Hz, 3H), 1.57–1.79 (m, 2H),
2.12–2.16 (m, 1H), 2.47–2.61 (m, 2H), 2.77–2.93 (m, 1H), 3.24–
3.38 (m, 2H), 3.39–3.47 (m, 3H), 3.49–3.80 (m, 9H), 4.04–4.24
(m, 3H). -IR (KBr): 3460, 1740, 1710, 1650 cm– 1. –HRMS (FAB)
Calcd. for C20H29N3O5S: 423.1828. Found 423.1821.
[15] N. Sato, F. Ohba, Drugs Future 1996, 21, 361–365.
[16] M. Sunagawa, M. Itho, K. Kubota, A. Sasaki, Y. Ueda, J. Anti-
biot. 2002, 55, 722–757.
[17] B. Nicolae, B. Constantin, B. Emila, C. Olga, B. Rom, Revis-
tade Chimie 1983, 34, 699–706.
[18] M. Solymar, E. Forro, F. Fulop, Tetrahedron Asymmetry 2004,
15, 3281–3287.
[19] C.-H. Oh, H.-W. Cho, J.-H. Cho, Eur. J. Med. Chem. 2006, 41,
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i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com