Synthesis and biological evaluation of 1β-methylcarbapenems having guanidino moieties

Article abstract of DOI:10.1016/j.ejmech.2004.12.009

The synthesis of a new series of 1β-methylcarbapenems having the substituted guanidinocarbonyl pyrrolidine moieties is described. Their in vitro antibacterial activities against both Gram-positive including MRSA and Gram-negative bacteria were tested and

Full text of DOI:10.1016/j.ejmech.2004.12.009

European Journal of Medicinal Chemistry 41 (2006) 50–55
http://france.elsevier.com/direct/ejmech
Original article
Synthesis and biological evaluation
of 1β-methylcarbapenems having guanidino moieties
Chang-Hyun Oh *, Jung-Hyuck Cho
Medicinal Chemistry Research Center, Korea Institute of Science and Technology, Seoul 130-650, South Korea
Received 9 September 2004; received in revised form 9 December 2004; accepted 13 December 2004
Available online 02 November 2005
Abstract
The synthesis of a new series of 1β-methylcarbapenems having the substituted guanidinocarbonyl pyrrolidine moieties is described. Their
in vitro antibacterial activities against both Gram-positive including MRSA and Gram-negative bacteria were tested and the effect of substi-
tuents on the pyrrolidine ring was investigated. In particular, the compound Ib having piperazinylguanidine moiety showed the most potent
antibacterial activity.
© 2005 Elsevier SAS. All rights reserved.
Keywords: 1β-Methylcarbapenems; Antibacterial activity; Substituent effects; Carbapenems
1. Introduction
agents with a broader spectrum of activity and anti-MRSA
activity.
Previously, we 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 potent
antibacterial activity, and a large number of derivatives have
been synthesized and investigated [7–13]. In our previous
work [13] the introduction of guanidine moieties showed po-
tent and well-balanced antibacterial activity including anti-
MRSA.
In this paper, we described the synthesis and structure–ac-
tivity relationships of the l β-methylcarbapenems having a 5′-
substituted guanidinocarbonyl pyrrolidin-3′-ylthio group as a
C-2 side chain and our approach for improvement of anti-
MRSA and antibacterial activity of the carbapenems is dis-
cussed.
A number of carbapenem antibiotics, for example imipe-
nem, 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-po-
sitive bacteria such as methicillin-resistant Staphylococcus
aureus (MRSA) and the Gram-negative pathogen Pseudomo-
nas aeruginosa, is relatively weak. During the past decade,
extensive synthetic efforts have been made to confer anti-
MRSA activity on β-lactams such as a cephalosporin [2] or
a carbapenem [3]. As a result, some cephalosporin and carba-
penem 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.
2. Results and discussion
From the literature of carbapenem antibiotics, especially
the SAR related to meropenem [4,5] and panipenem [6], the
importance of a pyrrolidine ring for potent activity and high
PBP affinity were noted. Thus we postulated that a combina-
tion of these two factors in a single side chain might lead to
2.1. Chemistry
Our general synthetic route leading to new carbapenems
involved the preparation of appropriately protected thiols con-
taining pyrrolidine ring as a side chain and subsequent cou-
pling reaction with the carbapenem diphenylphosphates, fol-
lowed by deprotection of the resulting protected carbapenems
* Corresponding author. Tel.: +82 2 958 5189.
E-mail address: choh@kist.re.kr (C.-H. Oh).
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2004.12.009

C.-H. Oh, J.-H. Cho / European Journal of Medicinal Chemistry 41 (2006) 50–55
51
Scheme 1.
in a usual manner. 2-(N-Substituted guanidinocarbonyl)-pyr-
rolidine derivatives (7a–h) were prepared by the sequence
crude products, which were purified by HP-20 column to give
the pure carbapenems (Ia–h) (Scheme 2).
shown in Scheme 1. N-Protected hydroxy- -proline methyl
L
ester (1) was converted to the O-mesylated compound 2 by
treatment of mesyl chloride and subsequently treated with so-
dium triphenyl methylthioate, which was generated in situ
from triphenylmethyl mercaptan and sodium hydride in
DMF, to provide 3 with inversion of the C-4 configuration.
The ester (3) was converted to the carboxylic acid 4 by treat-
ment of 4N-NaOH and subsequently treated with ethyl chlor-
oformate and 1H-pyrazole-1-carboxamidine to provide 5. Pre-
paration of the guanidine type compound (6a–h) was
accomplished by treatment of compound 5 with correspond-
ing cyclic amine. Deprotection of the trityl group to mercap-
tans (7a–h) was achieved by treatment of 6a–h with trifluor-
oacetic acid in the presence of triethylsilane (Scheme 1).
Finally, the reaction of 8 [14] with thiols (7a–h) in the
presence of diisopropylethylamine provided the correspond-
ing 2-substituted carbapenems (9a–h), respectively. Deprotec-
tion of these compounds by treatment of tetrakis(triphenyl-
phosphine)palladium(0) and tributyltin hydride gave the
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 per ml with the same
broth and inoculated with an inoculating device onto agar
containing serial twofold dilutions of the test compounds. Or-
ganisms were incubated at 37 °C for 18–20 hours. The MICs
of a compound were defined as the lowest concentration that
visibly inhibited growth.
2.2.2. Antibacterial activity studies
The in vitro antibacterial activities of the new carbapenems
(Ia–h) prepared above against Gram-positive and negative
bacteria including MRSA are listed in Tables 1 and 2. For
comparison, the MIC values of imipenem, meropenem and
vancomycin are also listed. Among these compounds, Ia,
Scheme 2.

52
C.-H. Oh, J.-H. Cho / European Journal of Medicinal Chemistry 41 (2006) 50–55
Table 1
In vitro antibacterial activities of carbapenem derivatives (Ia–h)
R =
IPMa
MPMb
Organism
Ia
Ib
Ic
Id
Ie
If
Ig
Ih
Streptococcus pyogenes 308A
<0.01
0.03
<0.01
0.01
<0.01
<0.01
<0.01
0.01
0.01
0.40
0.10
0.80
0.80
0.10
0.20
0.09
0.01
0.01
0.20
0.10
0.05
0.03
3.10
0.10
0.10
0.05
1.95
0.01
0.01
0.01
S. pyogenes 77A
<0.01
0.03
0.03
0.05
0.05
0.80
0.10
0.05
0.05
2.20
0.01
0.40
0.10
0.10
0.05
6.20
0.10
0.10
0.10
1.67
<0.01
0.03
0.03
0.05
0.05
1.50
0.10
0.05
0.05
2.31
0.03
0.05
0.05
0.05
0.05
6.20
0.10
0.10
0.10
1.54
<0.01
0.03
0.03
0.05
0.03
1.50
0.05
0.05
0.03
1.98
0.01
0.20
0.03
0.10
0.01
0.05
Streptococcus aureus SG 511
S. aureus 503
0.10
0.05
0.05
6.20
0.10
0.20
0.05
2.37
0.05
0.05
0.05
6.20
0.10
0.05
0.05
1.85
0.05
0.03
0.03
0.40
0.05
0.03
0.03
1.00
Escherichia coli DC O
E. coli 1507 E
P. aeruginosa 9027
Salmonella typhimurium
Enterobacter cloacae P 99
E. cloacae 1321 E
DHP-I
MIC (μg ml–1) determined by agar dilution method.
a
IPM = imipenem.
MPM = meropenem.
b
Table 2
system was based on a HP5989A MS Engine (Palo Alto, CA,
USA) mass spectrometer with a HP Model 59987A.
Anti-MRSA activities of Ia, Ib and Ie
Methicillin resistant strains Ia
Ib
1.563
Ie
0.391
Vancomycin
1.563
S. aureus LG001
S. aureus LG002
S. aureus Y8012954
S. aureus QRS179
S. aureus QRS241
S. aureus Hoechst208E
S. aureus KIST2
1.563
0.391
0.195
0.391
0.391
0.195
6.25
3.1. (2S,4R)-4-Mesyloxy-1-(allyloxycarbonyl)pyrrolidin-2-
carboxylic acid methyl ester (2)
0.195
0.195
0.391
0.391
0.195
6.25
0.098
0.049
0.195
0.195
0.098
1.56
0.781
0.781
0.781
0.781
0.781
0.781
0.781
A solution of 1 (92.5 g, 0.41 mol) and triethylamine
(65.0 ml, 0.49 mol) in dry CH2Cl2 (600 ml) was cooled to
0 °C under nitrogen and treated with methanesulfonyl chlor-
ide (56.0 g, 0.49 mol). The mixture was stirred at 0 °C for 1 h,
diluted with CH2Cl2 (500 ml), and washed with 10%
NaHCO3 and brine. The organic layer was dried over anhy-
drous Na2SO4. Evaporation of the solvent in vacuo gave a
crude residue, which was purified by silica gel column chro-
matography (EtOAc/n-hexane = 1:2) to give 2 (23.2 g,
S. aureus KIST5
0.781
0.195
0.781
Ib, Ie and Ih showed superior or similar antibacterial activity
against Gram-positive bacteria to meropenem, and exhibited
improved antibacterial activity against Gram-negative bacteria
than imipenem.
As to the substituent of the iminocarbamoyl side chain, the
compounds Ie and Ih having hydroxyl group were generally
more potent than the non-hydroxy compounds Id and Ig.
As expected, the piperazine compound Ib exhibited the
most potent and well balanced activity including the anti-
MRSA activity. Furthermore we observed that the thiomor-
pholine urea Ia is more potent than the morpholine urea Ic.
The stability [13] to DHP-I of most compounds was tested
and all the compounds were more stable than meropenem.
1
93.2%) as a pale yellow oil. H-NMR (CDCl3) δ 2.27 (m,
1H), 2.75 (m, 1H), 3.06 (s, 3H), 3.77 and 3.80 (2 s, 3H),
3.82–3.97 (m, 2H), 4.42 (m, 1H), 4.57 (d, 2H, J=5.8 Hz),
5.25 (m, 3H), 5.92 (m, 1H).
3.2. (2S,4S)-4-Tritylthio-1-(allyloxycarbonyl)pyrrolidin-2-
carboxylic acid methyl ester (3)
To a stirred solution of triphenylmethyl mercaptan (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 °C and
was stirred for 1 h at room temperature. To the resulting solu-
tion was added 2 (75.7 g, 0.25 mol) solution in dry DMF
(150 ml) at 0 °C 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 succes-
sively 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
3. Experimental part
Melting point (mp): Thomas Hoover apparatus, uncor-
rected. UV spectra: Hewlett–Packard 8451A UV–VIS spec-
trophotometer. IR spectra: Perkin–Elmer 16F-PC FT-IR.
NMR spectra: Varian Gemini 300 spectrometer, tetramethyl-
silane (TMS), as an internal standard. The mass spectrometry

C.-H. Oh, J.-H. Cho / European Journal of Medicinal Chemistry 41 (2006) 50–55
53
1
(EtOAc/n-hexane = 1:7) to give 3 (100.6 g, 82.5%) as a pale
yellow oil. H-NMR (CDCl3) δ 2.01 (m, 1H), 2.55 (m, 1H),
3.16 (bs, 1H), 3.54 (bs, 1H), 3.77 and 3.80 (2 s, 3H), 3.97 (m,
1H), 4.42 (m, 1H), 4.55 (d, 2H, J = 5.5 Hz), 5.26 (m, 2H),
5.98 (m, 1H) 7.23 (m, 9H), 7.48 (m, 6H).
6b: Yield 69.8%. H-NMR (CDCl3) δ 1.77 (bs, 1H), 2.28
(m, 1H), 2.76 (bs, 1H), 2.98 (bs, 1H), 3.45 (bs, 1H), 3.50–
3.74 (bs, 8H), 3.98 (m, 1H), 4.43 (bs, 2H), 5.04–5.26 (m,
2H), 5.85 (m, 1H), 7.23 (m, 9H), 7.46 (m, 6H), 7.67 (bs, 1H).
1
1
6c: Yield 76.6%. H-NMR (CDCl3) δ 1.79 (bs, 1H), 2.28
(m, 1H), 2.79 (bs, 1H), 3.04 (bs, 1H), 3.30–3.45 (bs, 5H),
3.51–3.64 (bs, 4H), 4.02 (m, 1H), 4.43 (bs, 2H), 5.06–5.23
(m, 2H), 5.89 (m, 1H), 7.23 (m, 9H), 7.46 (m, 6H), 7.97 (bs,
1H).
3.3. (2S,4S)-4-Tritylthio-1-(allyloxycarbonyl)pyrrolidin-2-
carboxylic acid (4)
6d: Yield 77.9%. 1H-NMR (CDCl3) δ 1.43–1.57 (bs, 4H),
1.60–1.98 (bs, 3H), 2.17 (bs, 1H), 2.77–2.89 (bs, 1H), 2.94–
3.01 (m, 1H), 3.09–3.38 (bs, 2H), 3.65–3.89 (bs, 4H), 4.26–
4.43 (bs, 2H), 5.04–5.26 (m, 2H), 5.70–5.85 (m, 1H), 7.24
(m, 9H), 7.45 (m, 6H), 8.07 (s, 1H).
To a solution of 3 (48.7 g, 0.10 mol) in MeOH (500 ml)
was added slowly 4N-NaOH (38 ml, 0.15 mol) at 0 °C and
was stirred for 5 h at room temperature. The mixture was
neutralized with 4N-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 water, and dry in air to give 4 (39.4 g,
1
6e: Yield 69.8%. H-NMR (CDCl3) δ 1.45–1.95 (bs, 5H),
2.17 (bs, 1H), 2.75–2.87 (bs, 1H), 2.94–3.01 (m, 1H), 3.09–
3.33 (bs, 3H), 3.65–3.89 (bs, 4H), 4.26–4.43 (bs, 2H), 5.04–
5.26 (m, 2H), 5.70–5.85 (m, 1H), 7.24 (m, 9H), 7.44 (m,
6H), 8.03 (s, 1H).
6f: Yield 58.7%. 1H–NMR (CDCl3) δ 1.77–1.90 (bs, 2H),
1.96 (bs, 1H), 2.28 (m, 1H), 2.77–3.01 (bs, 3H), 3.32–3.51
(bs, 4H), 4.05 (bs, 2H), 4.43 (bs, 2H), 5.04–5.26 (m, 2H),
5.80–5.89 (m, 1H), 7.24 (m, 9H), 7.45 (m, 6H), 8.06 (s, 1H).
6g: Yield 75.4%. 1H–NMR (CDCl3) δ 1.24–1.34 (bs, 2H),
1.74–1.95 (bs, 3H), 2.37 (m, 1H), 2.77–2.89 (bs, 1H), 2.94
(bs, 1H), 3.26–3.58 (bs, 5H), 3.99 (m, 1H), 4.43 (bs, 2H),
5.04–5.26 (m, 2H), 5.74–5.92 (m, 1H), 7.24 (m, 9H), 7.45
(m, 6H), 8.02 (bs, 1H).
6h: Yield 60.4%. 1H-NMR (CDCl3) δ 1.27–1.32 (bs, 2H),
1.74–2.01 (bs, 3H), 2.33 (m, 1H), 2.77–2.89 (bs, 1H), 2.94
(bs, 1H), 3.22–3.55 (bs, 4H), 3.96 (m, 1H), 4.21 (bs, 2H),
4.43 (bs, 2H), 5.04–5.26 (m, 2H), 5.70–5.90 (m, 1H), 7.24
(m, 9H), 7.45 (m, 6H), 8.01 (bs, 1H).
1
83.3%) as a white solid. M.p. 150–153 °C (dec.). H-NMR
(CDCl3) δ 1.98 (m, 1H), 2.75–2.82 (m, 1H), 3.01 (m, 1H),
3.55 (bs, 2H), 3.98 (m, 1H), 4.55 (d, 2H, J = 5.9 Hz), 5.25
(m, 2H), 5.90 (m, 1H), 7.27 (m, 9H), 7.47 (m, 6H).
3.4. (2S,4S)-2-[(Iminopyrazol-1-ylmethyl)carbamoyl]-4-
tritylthio-1-(allyloxycarbonyl)pyrrolidne (5)
A solution of 4 (23.7 g, 0.05 mol) and triethylamine
(7.4 ml, 0.055 mol) in dry CH2Cl2 (300 ml) was cooled to
0 °C under nitrogen and treated with ethyl chloroformate
(5.25 ml, 0.055 mol). The mixture was stirred at 0 °C for
30 min, added with 1H-pyrazole-1-carboxamidine hydro-
chloride (8.1 g, 0.055 mol) and strirred at 0 °C 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 (EtOAc/n-hexane = 1:4) to give 5
1
(25.3 g, 89.5%) as a pale yellow oil. H-NMR (CDCl3) δ
3.6. Allyl (1R,5S,6S)-6-[(1R)-hydroxyethyl]-2-{5-
[(iminothiomorpholin-1-ylmethyl)carbamoyl]-1-
(allyloxycarbonyl)pyrrolidin-3-ylthio}-1-
1.85 (m, 1H), 2.18–2.26 (m, 1H), 2.79–2.86 (bs, 1H), 3.06
(m, 1H), 3.15 (m, 1H), 4.05 (m, 1H), 4.50–4.62 (bs, 2H),
5.28 (m, 2H), 5.87 (m, 1H), 6.42 (s, 1H), 7.27 (m, 9H),
7.48 (m, 6H), 7.71 (d, 1H, J = 2.6 Hz), 8.37 (d, 1H,
J = 2.6 Hz), 9.51 (bs, 1H).
methylcarbapen-2-em-3-carboxylate (9a)
To a solution of 6a (0.60 g, 1.0 mmol) in CH2Cl2 (2 ml)
was added dropwise triethylsilane (0.13 g, 1.1 mmol) at 5 °C,
and then TFA (2 ml). After stirring for 30 min at room tem-
perature, the mixture was evaporated under reduced pressure.
The residue was dissolved with ethyl acetate and washed
with 10% NaHCO3, brine. The organic layer was concen-
trated in vacuo to give a residue (7a), which was used with-
out further purification. A solution of allyl (1R,5S,6S)-2-(di-
phenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcar-
bapen-2-em-3-carboxylate (8, 0.50 g, 1.0 mmol) in CH3CN
(10 ml) was cooled to 0 °C under N2. To this solution was
added diisopropylethyl amine (0.13 g, 1.0 mmol) and a solu-
tion of the mercapto compound 7a in CH3CN (5 ml). After
stirring for 5 h, the mixture was diluted with ethyl acetate,
washed with 10% NaHCO3, brine, and dried over anhydrous
MgSO4. Evaporation in vacuo gave a foam, which was pur-
ified by silica gel chromatography (EtOAc/n-hexane = 1:1) to
3.5. (2S,4S)-2-[(Iminothiomorpholin-1-ylmethyl)carbamoyl]-
4-tritylthio-1-(allyloxycarbonyl) pyrrlidine (6a)
To a solution of 5 (1.00 g, 1.8 mmol) in THF (30 ml) was
added thiomorpholine (0.23 g, 2.2 mmol) at room tempera-
ture and was stirred for 3 h at the reflux. The mixture was
concentrated in vacuo to give a residue, which was purified
by silica gel column chromatography (EtOAc/n-hex-
ane = 1:1) to give 6a (0.87 g, 80.5%) as a pale yellow oil.
1H-NMR (CDCl3) δ 1.78 (bs, 1H), 2.09–2.16 (m, 1H), 2.55–
2.88 (bs, 6H), 3.08 (bs, 1H), 3.25–3.44 (bs, 4H), 3.95 (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), 8.01 (s, 1H).
Compounds 6b–h from 5 were carried out by the same
procedure as described for the preparation of 6a.

54
C.-H. Oh, J.-H. Cho / European Journal of Medicinal Chemistry 41 (2006) 50–55
1
give 9a (0.39 g, 61.5%) as a yellow amorphous solid. H-
NMR(CDCl3) δ 1.20 (d, 3H, J = 7.0 Hz), 1.27 (d, 3H,
J = 6.2 Hz), 1.58 (bs, 1H), 1.96 (bs, 1H), 2.46–2.80 (bs,
5H), 3.10 (bs, 1H), 3.25–3.36 (m, 2H), 3.49–3.59 (bs, 1H),
3.71–3.88 (bs, 4H), 3.95 (m, 1H), 4.10–4.23 (bs, 2H), 4.40–
4.52 (bs, 2H), 4.55 (dd, 1H, J = 5.2 and 5.6 Hz), 4.68 (dd,
1H, J = 5.2 and 5.6 Hz), 5.12–5.50 (m, 4H), 5.65–6.01 (bs,
2H), 7.60 (bs, 1H).
3.7. (1R,5S,6S)-6-[(1R)-Hydroxyethyl]-2-{5-
[(iminothiomorpholin-1-ylmethyl)carbamoyl]pyrro lidin-3-
ylthio}-1-methylcarbapen-2-em-3-carboxylic acid (Ia)
To a stirred solution of 9a (0.20 g, 0.33 mol) and
Pd(PPh3)4 (30 mg) in CH2Cl2 (5 ml) was added dropwise
n-tributytin hydride (0.18 ml, 0.66 mmol) at 0 °C and was
stirred for 1 h at same temperature. To the resulting solution
was diluted with water (10 ml) and the organic layers was
washed with water (2 × 10 ml). The combined aqueous layers
were washed with ethyl ether (2 × 10 ml) and lyophilized to
give a yellow powder which was purified on a Diaion HP-20
column, eluting with 2% THF in water. Fractions having UV
absorption at 298 nm were collected and lyophilized again to
give the title compound Ia as a amorphorus solid. Yield
The synthesis of compounds 9b–h were carried out by the
same procedure as described for the preparation of 9a.
9b: Yield 63.9%. 1H-NMR(CDCl3) δ 1.26 (d, 3H,
J = 7.0 Hz), 1.35 (d, 3H, J = 6.2 Hz), 1.68 (bs, 1H), 2.03
(bs, 1H), 2.80 (bs, 1H), 3.13 (bs, 1H), 3.35–3.46 (m, 3H),
3.59–3.79 (bs, 10H), 3.95 (m, 1H), 4.18–4.23 (bs, 2H),
4.40–4.52 (bs, 1H), 4.55 (bs, 2H), 4.59 (m, 1H), 4.78 (m,
2H), 5.12–5.50 (m, 4H), 5.65–6.01 (bs, 3H), 7.68 (bs, 1H).
9c: Yield 64.3%. 1H-NMR(CDCl3) δ 1.22 (d, 3H,
J = 7.0 Hz), 1.29 (d, 3H, J = 6.2 Hz), 1.61 (bs, 1H), 2.02
(bs, 1H), 2.46 (bs, 1H), 3.10 (bs, 1H), 3.25–3.39 (m, 6H),
3.49–3.59 (bs, 1H), 3.71–3.88 (bs, 4H), 3.95 (m, 1H),
4.10–4.23 (bs, 2H), 4.40–4.52 (bs, 2H), 4.55 (bs, 1H), 4.68
(bs, 1H), 5.13–5.45 (m, 4H), 5.69–6.00 (bs, 2H), 7.70 (bs,
1H).
9d: Yield 72.5%. 1H-NMR(CDCl3) δ 1.28 (d, 3H,
J = 7.0 Hz), 1.37 (d, 3H, J = 6.1 Hz), 1.43–1.57 (bs, 4H),
1.60–1.98 (bs, 3H), 1.98 (m, 1H), 2.46 (bs, 1H), 3.10 (bs,
1H), 3.25–3.39 (m, 2H), 3.49–3.69 (bs, 5H), 3.95 (m, 1H),
4.10–4.23 (bs, 2H), 4.40–4.52 (bs, 2H), 4.55 (bs, 1H), 4.68
(bs, 1H), 5.13–5.45 (m, 4H), 5.69–6.00 (bs, 2H), 7.70 (bs,
1H).
9e: Yield 69.9%. 1H-NMR(CDCl3) δ 1.25 (d, 3H,
J = 7.0 Hz), 1.32 (d, 3H, J = 6.1 Hz), 1.43–1.57 (bs, 2H),
1.60–1.98 (bs, 3H), 1.98 (m, 1H), 2.46 (bs, 1H), 3.10 (bs,
1H), 3.25–3.39 (m, 2H), 3.49–3.69 (bs, 5H), 3.80 (bs, 1H),
3.95 (m, 1H), 4.10–4.20 (bs, 2H), 4.40–4.52 (bs, 2H), 4.55
(bs, 1H), 4.68 (bs, 1H), 5.10–5.49 (m, 4H), 5.69–6.00 (bs,
2H), 7.80 (bs, 1H).
9f: Yield 65.9%. 1H-NMR(CDCl3) δ 1.15 (d, 3H,
J = 7.0 Hz), 1.26 (d, 3H, J = 6.1 Hz), 1.37–1.57 (bs, 2H),
1.66 (bs, 1H), 1.98 (m, 1H), 2.40 (bs, 1H), 3.10 (bs, 1H),
3.25–3.39 (m, 3H), 3.49–3.61 (bs, 4H), 3.80 (bs, 1H), 3.95
(m, 1H), 4.10–4.20 (bs, 2H), 4.26–4.72 (bs, 4H), 4.95 (bs,
1H), 5.10–5.49 (m, 4H), 5.69–6.00 (bs, 2H), 7.80 (bs, 1H).
9 g: Yield 65.5%. 1H-NMR(CDCl3) δ 1.28 (d, 3H,
J = 7.0 Hz), 1.37 (d, 3H, J = 6.1 Hz), 1.43–1.57 (bs, 2H),
1.60–1.88 (bs, 3H), 1.98 (m, 1H), 2.46 (bs, 1H), 3.10 (bs,
1H), 3.20–3.44 (m, 4H), 3.49–3.69 (bs, 4H), 3.95 (m, 1H),
4.10–4.23 (bs, 1H), 4.26–4.68 (bs, 4H), 5.13–5.47 (m, 4H),
5.70–5.98 (bs, 2H), 7.70 (bs, 1H).
1
18.8%. UV λmax: 298 nm. H-NMR (D2O) δ 0.97 (d, 3H,
J = 5.3 Hz), 1.06 (d, 3H, J = 6.3 Hz), 1.98 (bs, 1H), 2.48–
2.57 (bs, 2H), 2.65–2.74 (m, 2H), 3.11–3.28 (bs, 4H), 3.53–
3.65 (bs, 2H), 3.70–3.88 (bs, 3H), 3.96 (t, 2H, J = 9.1 Hz),
4.11 (m, 1H), 4.42 (m. 1H). IR (KBr): 3480, 1745, 1710,
1660, 1610 (C=NH) cm−1. HRMS(FAB) Calc. for C20H29N
5O5S2 483.1610, Found 483.1612.
The synthesis of compounds Ib–h were carried out by the
same procedure as described for the preparation of Ia.
1
Ib: Yield 14.7%. UV λmax: 298 nm. H-NMR (D2O) δ
1.05 (d, 3H, J = 7.1 Hz), 1.18 (d, 3H, J = 6.5 Hz), 1.80 (m,
1H), 2.47 (m,2H), 2.97 (bs, 4H), 3.23 (bs, 2H), 3.28–3.30 (m,
1H), 3.54 (dd, 1H, J = 5.2 and 5.6 Hz), 3.59 (bs, 1H), 3.65–
3.88 (bs, 3H), 4.10 (m, 2H), 4.19 (dd, 1H, J = 4.5 and
2.2 Hz). IR (KBr): 3460, 1740, 1710, 1670, 1610 (C=NH)
cm−1. HRMS(FAB) Calc. for C20H30N6O5S 466.1998,
Found 466.1998.
1
Ic: Yield 17.3%. UV λmax : 298 nm. H-NMR (D2O) δ
1.01 (d, 3H, J = 5.5 Hz), 1.06 (d, 3H, J = 6.7 Hz), 1.88
(bs, 1H), 2.48–2.59 (bs, 2H), 3.09–3.38 (bs, 5H), 3.53–3.65
(bs, 2H), 3.66–3.96 (m, 6H), 4.11 (m, 1H), 4.42 (m. 1H). IR
(KBr): 3430, 1720, 1710, 1660, 1610 (C=NH) cm−1. HRMS
(FAB) Calc. for C20H29N5O6S 467.1839, Found 467.1837.
1
Id: Yield 20.2%. UV λmax : 298 nm. H-NMR (D2O) δ
1.01 (d, 3H, J = 7.0 Hz), 1.10 (d, 3H, J = 6.2 Hz), 1.40–1.57
(bs, 4H), 1.62–1.99 (bs, 3H), 2.45–2.56 (bs, 2H), 2.96–3.18
(bs. 2H), 3.21–3.44 (bs, 2H), 3.60–3.83 (bs, 5H), 4.14 (bs,
1H), 4.49 (m. 1H). IR (KBr): 3400, 1755, 1700, 1670, 1620
(C=NH) cm−1. HRMS(FAB) Calc. for C21H31N5O5S
465.2046, Found 465.2041.
1
Ie: Yield 13.6%. UV λmax : 298 nm. H-NMR (D2O) δ
0.96 (d, 3H, J = 6.9 Hz), 1.06 (d, 3H, J = 6.2 Hz), 1.29–
1.37 (bs, 2H), 1.50–1.69 (bs, 2H), 1.77–1.96 (bs, 2H), 2.44
(m, 2H), 3.03–3.10 (bs, 2H), 3.34–3.50 (bs, 2H), 3.64–3.79
(bs, 4H), 3.95 (bs, 1H), 4.16 (bs, 1H), 4.45 (m. 1H). IR
(KBr): 3390, 1720, 1700, 1680, 1625 (C=NH) cm−1.
HRMS(FAB) Calc. for C21H31N5O6S 481.1995, Found
481.1994.
9h: Yield 68.4%. 1H-NMR(CDCl3) δ 1.22 (d, 3H,
J = 6.7 Hz), 1.30 (d, 3H, J = 6.2 Hz), 1.36 (bs, 2H), 1.74–
2.01 (bs, 3H), 2.35 (bs, 1H), 3.11 (bs, 1H), 3.23–3.38 (m,
3H), 3.42–3.51 (bs, 3H), 3.80 (bs, 1H), 3.90–4.03 (m, 3H),
4.09–4.21 (bs, 2H), 4.26–4.76 (bs, 4H), 5.10–5.51 (m, 4H),
5.69–6.00 (bs, 2H), 7.80 (bs, 1H).
1
If: Yield 11.9%. UV λmax : 298 nm. H-NMR (D2O) δ
1.06 (d, 3H, J = 6.6 Hz), 1.13 (d, 3H, J = 6.1 Hz), 1.37–
1.53 (bs, 2H), 1.98 (m, 1H), 2.46 (m, 1H), 2.79–2.85 (m,

C.-H. Oh, J.-H. Cho / European Journal of Medicinal Chemistry 41 (2006) 50–55
55
[2] a) H. Hanaki, H. Akagi, S. Nomura, N. Unemi, J. Antibiot. 49 (1996)
402–404. b) O. K. Kim, Y. Udea, M. Mansuri, J. W. Russel, Bioorg.
Med. Chem. Lett. 7 (1997) 1945–1950.
1H), 3.01–3.16 (bs, 2H), 3.28–3.44 (bs, 3H), 3.54–3.65 (bs,
2H), 3.69 (m, 1H), 3.99 (bs, 1H), 4.13 (bs, 1H), 4.40 (m.
1H), 7.90 (s, 1H). IR (KBr): 3390, 1720, 1690, 1680, 1610
(C=NH) cm−1. HRMS(FAB) Calc. for C20H28N6O5S
464.1842, Found 464.1840.
[3] a) L. C. Waddel, R. W. Ratcliffe, S. P. Szumiloski, K. J. Wildonger, J.
K. Huber, G. G. Hamond, Bioorg. Med. Chem. Lett. 5 (1995) 1427–
1432. b) H. Shinagawa, H. Yamaga, H. Houchigai, Y. Sumita, M. Su-
naga, Bioorg. Med. Chem. 5 (1997) 601–621.
1
Ig Yield 19.2%. UV λmax : 298 nm. H-NMR (D2O) δ
1.07 (d, 3H, J = 7.0 Hz), 1.17 (d, 3H, J = 6.2 Hz), 1.43–
1.57 (bs, 2H), 1.60–1.88 (bs, 3H), 2.45–2.53 (m, 1H), 2.88
(bs, 1H), 3.15–3.38 (bs, 4H), 3.49–3.73 (bs, 3H), 3.91
(m,1H), 4.06–4.12 (bs, 2H), 4.40 (m. 1H). IR (KBr): 3400,
1730, 1710, 1680, 1625 (C=NH) cm−1. HRMS(FAB) Calc.
for C20H29N5O5S 451.1889, Found 451.1890.
[4] Y. Fukasawa, T. Okuda, J. Antibiot. 43 (1990) 314–320.
[5] M. Sunagawa, H. Matsumure, T. Inoue, M. Fukasawa, M. Kato, J.
Antibiot. 43 (1990) 519–532.
[6] T. Miyadera, T. Sugimura, T. Hasimoto, T. Tanaka, K. Iino, S. Suga-
wara, J. Antibiot. 36 (1983) 1034–1039.
[7] C.-H. Oh, J.-H. Cho, J. Antibiot. 47 (1994) 126–128.
1
Ih Yield 14.0%. UV λmax : 298 nm. H-NMR (D2O) δ
[8] C.B. Jin, I.S. Jung, H.-J. Ku, J.W. Yook, D.-H. Kim, J.-H. Cho, M.S.
1.03 (d, 3H, J = 6.7 Hz), 1.10 (d, 3H, J = 6.2 Hz), 1.36–
1.44 (bs, 2H), 1.68–1.96 (bs, 3H), 2.46 (m, 1H), 2.85 (m,
1H), 3.05–3.19 (bs, 2H), 3.45–3.54 (bs, 2H), 3.60–3.78 (bs,
4H), 3.95–4.08 (bs, 2H), 4.18 (m, 1H), 4.39 (m. 1H). IR
(KBr): 3390, 1740, 1715, 1680, 1620 (C=NH) cm−1.
HRMS(FAB) Calc. for C21H31N5O6S 481.1995, Found
481.1991.
Kim, C.-H. Oh, Toxicology 138 (1999) 59–67.
[9] C.-H. Oh, H.-W. Cho, I.-K. Lee, J.-Y. Gong, J.-H. Choi, J.-H. Cho,
Arch. Pharm. Pharm. Med. Chem. 335 (2002) 152–158.
[10] C.-H. Oh, H.-G. Dong, H.-W. Cho, S.J. Park, J.H. Hong, J.-H. Cho,
Arch. Pharm. Pharm. Med. Chem. 335 (2002) 200–206.
[11] C.-H. Oh, H.-W. Cho, J.-H. Cho, Eur, J. Med. Chem. 37 (2002) 743–
754.
[12] C.-H. Oh, S.-C. Lee, J.-H. Cho, Eur, J. Med. Chem. 38 (2003) 751–
758.
References
[13] C.-H. Oh, S.-C. Lee, J.-H. Cho, Eur, J. Med. Chem. 38 (2003) 841–
850.
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