Novel lβ-methylcarbapenems having cyclic sulfonamide moieties: Synthesis and evaluation of in-vitro biological activity - Part II

Article abstract of DOI:10.1002/ardp.200800226

The synthesis of a new series of 1β-methylcarbapenems having cyclic sulfonamide moieties is described. Their in-vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of a substituent on the pyrroli

Full text of DOI:10.1002/ardp.200800226

528
Arch. Pharm. Chem. Life Sci. 2009, 342, 528–532
Full Paper
Novel lb-Methylcarbapenems Having Cyclic Sulfonamide
Moieties: Synthesis and Evaluation of in-vitro Biological
Activity – Part II
Seong Jong Kim, Jung-Hyuck Cho, and Chang-Hyun Oh
Biomaterials Research Center, Korea Institute of Science and Technology, Seoul, Korea
The synthesis of a new series of 1b-methylcarbapenems having cyclic sulfonamide moieties is
described. Their in-vitro antibacterial activities against both Gram-positive and Gram-negative
bacteria were tested and the effect of a substituent on the pyrrolidine ring was investigated. One
particular compound IIIe having a [1,2,5]thiadiazolidin 1,1-dioxide moiety showed the most
potent antibacterial activity.
Keywords: Antibacterial activity / 1b-Methylcarbapenems / Substituent effects /
Received: December 11, 2008; accepted: March 24, 2009
DOI 10.1002/ardp.200800226
Introduction
Results and discussion
Chemistry
Carbapenems are one of the most potent types of antibac-
terial agents and are, among those, used as a last resort
against infections in the clinical field. Three carbape-
nems, imipenem [1, 2], meropenem 1 [3] (Fig. 1), and erta-
penem 2 [4] (Fig. 1) have been marketed so far. At present,
several carbapenem derivatives such as S-4661 3 [5]
(Fig. 1), BO-2727 [6], and E-1010 [7] are under clinical or
preclinical studies since the launch of meropenem.
We have also reported that the carbapenem com-
pounds having a pyrrolidin-3-yl-thio group at the C-2
position in the carbapenem skeleton are noted for their
broad and potent antibacterial activity, and a large num-
ber of derivatives have been synthesized [8–13]. In this
paper, we describe the synthesis and structure-activity
relationships of lb-methylcarbapenems having a 59-cyclic
sulfonamide moieties at a C-2 side chain and our
approach for improvement of antibacterial activity of
the carbapenems is discussed.
Our general synthetic route leading to new carbapenems
involved the preparation of appropriately protected thi-
ols containing a pyrrolidine ring as a side chain and sub-
sequent coupling reaction with the carbapenem diphe-
nylphosphates, followed by deprotection of the resulting
protected carbapenems in a usual manner.
The substituted sulfamides 3a–d, g were easily accessi-
ble by the condensation of the corresponding diamines
1a–d, g with sulfamide itself in refluxing pyridine
(Scheme 1) [13].
The other cyclic sulfamides 3e and 3f were also synthe-
sized by the improved procedure shown in Scheme 2.
The intermediates 4e and 4f were directly synthesized by
reaction of the corresponding mustards with N-(t-butoxy-
carbonyl)sulfamoyl chloride. The N-Boc cyclosulfamides
3e and 3f were obtained in high yield by treatment of 4e
and 4f with K2CO3 in DMSO [13].
Compounds 7a–g were obtained by treatment of car-
boxylic acids 5 and 3a–g using oxalyl chloride. Deprotec-
tion of the trityl group to mercaptans Ia–g were achieved
by treatment of 7a–g with trifluoroacetic acid in the
presence of triethylsilane (Scheme 3).
Correspondence: Chang-Hyun Oh, Biomaterials Research Center, Ko-
rea Institute of Science and Technology, Seoul 130-650, Korea.
E-mail: choh@kist.re.kr
Finally, the reaction of 8 [14] with thiols Ia–g in the
presence of diisopropylethylamine provided the 2-substi-
Fax: +82 2 958-5189
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2009, 342, 528–532
Novel lb Methylcarbapenems with Cyclic Sulfonamide Moieties
529
Figure 1. Structures of meropenem, ertapenem, and S-4661.
Scheme 1. Synthesis of compounds 3a–d, g.
Scheme 3. Synthesis of compounds Ia–g.
Scheme 2. Synthesis of the compounds 3e and 3f.
tuted carbapenems 11a–g. Deprotection of these com-
pounds was carried out by tetrakis(triphenylphosphine)-
palladium(0) and tributyltin hydride to give the crude
products, which were purified on a HP-20 column to give
the pure carbapenems IIIa–g (Scheme 4).
Scheme 4. Synthesis of compounds IIIa–g.
tive bacteria to imipenem, in particular, against Escheri-
chia coli, Klebsiella peneumoniae, Citrobacter freundii, and
Enterobactor cloaca. Most of the compounds except com-
pound IIId showed to be 2–4 times more active than imi-
penem.
By comparing the effect of at C-5 of the pyrrolidine side
chain on the activity, it was found that compounds IIIf–
g having thiadiazinane moieties showed minor differen-
ces in activity compared to the thiadiazolidine com-
pounds IIIa, e.
The introduction of an alkyl group at the N-position of
thiadiazolidines IIIa, b led to a significantly enhanced
antibacterial activity compared to compounds IIIc, d
with an alkyl substitute at the C-3 position. With increas-
ing order of bulkiness of the groups from hydrogen,
methyl, ethyl to dimethyl in compounds Ie, Ia, Ib, Ic, and
Id, respectively, it was found that their activities
decreased. It could be revealed that any bulky substituent
Biological activity
The MICs were determined by the agar dilution method
using test agar. An overnight culture of bacteria in tryp-
tosoy broth was diluted to about 106 cells/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 378C for 18–
20 hours. The MICs of a compound were defined as the
lowest concentration that visibly inhibited growth.
The in-vitro antibacterial activities of new carbapenems
(sustituents IIIa–g) prepared above against both Gram-
positive and Gram-negative bacteria are listed in Table 1.
For comparison, the MIC values of imipenem and mero-
penem are also listed. All the compounds displayed supe-
rior or similar antibacterial activities against Gram-nega-
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

530
S. J. Kim et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 528–532
Table 1. In-vitro antibacterial activity(MIC, lg/mL) of the carbapenem derivatives IIIa–g.
STRAINS
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IPMa)
MPMb)
Staphylococcus aureus 1218
Coagulase negative staphylococci
Enterococcus faecalis 2347
Streptococcus pyogenes 9889
Streptococcus agalaciae 32
Streptococcus pneumoniae 0025
Haemophilus influenzae 1210
Escherichia coli 04
Klebsiella peneumoniae 523
Citrobacter freundii 323
Enterobactor cloacae 34
Serratia marcescens 3349
Acinetobacter baumannii 2289
Psudemonas aeruginosa 5455
6.25
0.390
6.25
12.5
6.25
0.390
25.0
0.049
0.049
0.049
25.0
3.125
0.098
6.25
6.25
0.781
12.5
0.025
0.098
0.049
6.25
0.025
0.098
0.025
0.098
0.198
12.5
1.563
0.025
1.56
a0.01
0.01
6.25
0.098
12.50
0.013
0.049
0.010
3.125
0.049
0.025
0.025
0.025
0.049
12.5
1.563
12.5
0.025
0.098
0.049
0.781
12.5
0.049
0.098
0.049
1.563
12.5
0.025
0.098
0.049
6.25
0.049
0.098
0.049
0.098
0.198
6.25
0.049
0.049
0.049
3.125
0.049
0.198
0.049
0.098
0.198
0.025
0.025
0.049
6.25
0.049
0.098
0.025
0.049
0.098
a0.01
6.25
12.5
12.5
12.5
0.098
0.391
0.098
0.198
0.781
0.098
0.198
0.198
0.198
0.391
0.098
1.563
0.198
0.391
0.781
0.198
0.781
0.390
0.781
0.781
12.5
12.5
1.563
25.0
3.125
12.5
3.125
25.0
6.25
12.5
0.781
12.5
0.391
0.781
3.125
1.563
a)
imipenem
meropenem
b)
at 08C and was stirred for 1 h at room temperature. To the result-
ing solution was added 6 solution in dry DMF (10 mL) at 08C and
was stirred for 8 h at room temperature. The mixture was
diluted with water and extracted with ethyl acetate. The organic
layer was successively washed with water and dried over anhy-
drous Na2SO4. Evaporation of the solvent in vacuo gave a crude
residue, which was purified by silica gel column chromatogra-
phy (EtOAc / n-hexane = 1 : 1) to give 7a (0.52 g, 47%) as a pale
yellow oil.
(Ic and Id) led to a significant loss in antibacterial activ-
ity, which suggests that the bulky substituents are not
favorable.
As a result, among all of these derivatives, compound
IIIe having a [1,2,5]thiadiazolidin 1,1-dioxide moiety
showed the most potent antibacterial activity while the
thiadiazinane-substituted compounds IIIf, g exhibited a
more potent activity against Psudemonas aeruginosa than
imipenem and meropenem.
Compound 7a
1H-NMR (CDCl3) d: 1.71–1.79 (m, 2H), 2.29–2.46 (m, 1H), 2.79 (s,
3H), 2.90 (d, J = 6.1 Hz, 2H), 3.66–3.72 (m, 1H), 3.87 (bs, 2H),
4.37–4.53 (m, 2H), 5.13–5.29 (m, 2H), 5.73–5.90 (m, 1H), 7.32–
7.22 (m, 9H), 7.43 (d, J = 9.5 Hz, 6H). 13C-NMR (CDCl3) d: 30.73,
31.13, 33.01, 42.11, 39.64, 51.24, 52.81, 55.78, 66.87, 118.30,
128.82, 129.02, 135.54, 136.76, 142.61, 179.21.
We would like to thank Hawon Pharmaceuticals Co., which
supported us with funds and also thank Mrs. Seo Sun Hee for
performing antibacterial tests.
The authors have declared no conflict of interest.
The synthesis of compounds 7b–g were carried out by the
same procedure as described for the preparation of 7a
Experimental
Compound 7b
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: Var-
ian Gemini 300 spectrometer (Varian, Inc., Palo Alto, CA, USA),
tetramethylsilane (TMS), as an internal standard. The mass spec-
trometry system was based on a HP5989A MS Engine mass spec-
trometer with a HP Model 59987A (both Hewlett Packard).
Yield: 52%. 1H-NMR (CDCl3) d: 1.60 (s, 3H), 1.72–1.84 (m, 1H),
2.31–2.48 (m, 2H), 3.08–3.16 (m, 3H), 3.36–3.86 (m, 3H), 3.46–
3.48 (d, J = 6.0 Hz, 2H), 3.87 (bs, 1H), 4.42–4.50 (m, 2H), 5.19–5.23
(m, 2H), 5.80–5.89 (m, 1H), 7.14-7.31 (m, 9H), 7.43 (d, J = 7.2 Hz,
6H). 13C-NMR (CDCl3) d: 15.29, 37.12, 39.16, 41.86, 46.29, 46.45,
46.94, 52.20, 62.56, 66.85, 116.27, 126.19, 130.28, 133.24, 135.46,
146.06, 176.84.
Chemistry
(2S,4S)-2-[(5-Methyl-1,1-dioxo-[1,2,5]thiadiazolidin-2-
Compound 7c
1
yl)carbonyl]-4-tritylthio-1-(allyloxycarbonyl)pyrrolidine 7a
To solution of 5 (1.0 g, 2.1 mmol) in dry CH2Cl2 (50 mL) was added
drop-wise oxalyl chloride (0.60 mL, 6.3 mmol) and was stirred
for 2 h at room temperature. The mixture was evaporated under
reduced pressure to give crude 6. To a stirred solution of cyclic
sulfamide (3a, 0.30 g, 2.2 mmol) in dry DMF (40 mL) was added
dropwise sodium hydride (0.12 g, 3.1 mmol, 60% oil suspension)
Yield: 46%. H-NMR (CDCl3) d: 1.33 (s, 3H), 1.68–1.66 (m, 2H),
2.73–2.78 (m, 1H), 2.94–2.97 (m, 1H), 3.22 (q, 1H), 3.40–3.47 (m,
1H), 3.65–3.67 (m, 1H), 3.81 (bs, 1H), 4.18–4.06 (m, 1H), 4.41–
4.35 (m, 2H), 4.45 (bs, 1H), 5.01–5.18 (m, 2H), 5.71–5.82 (m, 1H),
7.25-7.12 (m, 9H), 7.36 (d, J = 7.5 Hz, 6H). 13C-NMR (CDCl3) d: 22.94,
34.42, 39.66, 46.02, 46.85, 52.02, 60.17, 66.79, 66.95, 114.32,
126.32, 129.28, 133.10, 150.59, 156.18, 172.48.
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2009, 342, 528–532
Novel lb Methylcarbapenems with Cyclic Sulfonamide Moieties
531
Compound 7d
Compound IIa
Yield: 47%. 1H-NMR (CDCl3) d: 1.46 (s, 6H), 1.60–1.87 (m, 3H),
2.26–2.47 (m, 1H), 2.81–2.87 (m, 1H), 3.79 (s, 1H), 3.84 (s, 1H),
4.10–4.18 (m, 1H), 4.44–4.49 (m, 2H), 4.64–4.70 (m, 2H), 5.16–
5.25 (m, 2H), 7.20–7.32 (m, 9H), 7.43 (d, J = 7.0 Hz, 6H). 13C-NMR
(CDCl3) d: 30.29, 35.42, 40.96, 46.32, 48.20, 48.92, 52.10, 57.19,
61.11, 66.75, 116.32, 120.28, 133.10, 150.28, 153.18, 172.39.
1H-NMR (CDCl3) d: 1.24 (d, J = 7.5 Hz, 3H), 1.26 (d, J = 6.5 Hz, 3H),
1.99–2.04 (m, 1H), 2.81 (s, 2H), 3.25 (bs, 1H), 3.40–3.49 (m, 5H),
3.74 (bs, 1H), 3.09–4.02 (m, 2H), 4.16–4.18 (m, 3H), 4.55–4.59
(m, 4H), 4.71 (dd, J = 5.6 and 6.1 Hz, 1H), 4.80 (dd, J = 5.5 and
6.0 Hz, 1H), 5.24–5.47 (m, 4H), 4.57 and 5.42 (2s, 1H), 5.92-5.98
(m, 2H).
The synthesis of compounds IIb–g were carried out by the
same procedure as described for the preparation of IIa.
Compound 7e
Yield: 65%. 1H-NMR (CDCl3) d: 1.53 (s, 9H), 2.16 (s, 1H), 2.14–2.20
(m, 1H), 2.79 (bs, 1H), 2.79–3.09 (m, 2H), 3.42–3.49 (m, 2H), 3.86
(t, J = 12.8 Hz, 2H), 4.03–4.15 (m, 2H), 4.49–4.54 (m, 2H), 5.09–
5.28 (m, 3H), 5.75–5.90 (m, 1H), 7.19–7.31 (m, 9H), 7.44 (d, J =
7.0 Hz, 6H). 13C-NMR (CDCl3) d: 38.16, 42.94, 46.29, 48.20, 52.07,
54.25, 62.15, 68.85, 117.32, 124.32, 116.32, 127.51, 127.72,
127.18, 129.28, 131.22, 142.71, 167.14.
Compound IIb
Yield: 36%. 1H-NMR (CDCl3) d: 1.23–1.31 (m, 6H), 1.59 (s, 3H), 2.94
(bs, 2H), 3.14–3.18 (m, 3H), 3.40–3.48 (m, 3H), 3.74–3.75 (m, 1H),
3.85–3.97 (m, 3H), 4.08–4.13 (m, 2H), 4.58–4.64 (m, 4H), 4.67
(dd, J = 5.2 and 10.2 Hz, 1H), 4.71 (dd, J = 6.2 and 10.2 Hz, 1H),
4.98–5.01 (m, 1H), 5.14–5.32 (m, 4H), 5.87–5.95 (m, 2H).
Compound IIc
1
Yield: 40%. H-NMR (CDCl3) d: 1.23–1.34 (m, 6H), 1.90–1.98 (m,
Compound 7f
1
2H), 2.17 (s, 3H), 2.57–2.71 (m, 2H), 3.11–3.25 (m, 1H), 3.25–3.49
(m, 3H), 3.60–3.69 (m, 1H), 4.07–4.09 (m, 1H), 4.15–4.26 (m, 2H),
4.54–4.71 (m, 4H), 4.74 (dd, J = 5.3 and 11.2 Hz, 1H), 4.80 (dd, J =
6.1 and 10.1 Hz, 1H), 5.20–5.34 (m, 4H), 5.41 and 5.47 (2s, 1H),
5.89–5.95 (m, 2H).
Yield: 47%. H-NMR (CDCl3) d: 1.52 (s, 9H), 1.88–1.92 (m, 2H),
2.31–2.56 (m, 2H), 2.77–2.94 (m, 2H), 3.04–3.24 (m, 1H), 3.62–
3.66 (m,1H), 3.93–4.10 (m, 3H), 4.38–4.50 (m, 2H), 4.96–5.01 (m,
1H), 5.04–5.29 (m, 2H), 5.77–5.91 (m, 1H), 7.19–7.36 (m, 9H),
7.44 (d, J = 6.9 Hz, 6H). 13C-NMR (CDCl3) d: 26.14, 30.18, 37.23,
41.02, 46.39, 48.31, 52.07, 53.36, 56.92, 67.94, 68.76, 81.92,
116.32, 126.19, 127.51, 130.58, 133.10, 153.28, 153.17, 176.03.
Compound IId
Yield: 23%. 1H-NMR (CDCl3) d: 1.24–1.31 (m, 6H), 1.62 (s, 6H),
2.92–3.03 (m, 2H), 3.26–3.28 (m, 1H), 3.35–3.51 (m, 2H), 3.77–
3.88 (m, 3H), 4.03–4.17 (m, 2H), 4.22–4.28 (m, 1H), 4.55–4.73
(m, 4H), 4.80 (dd, J = 5.2 and 10.2 Hz, 1H), 4.87 (dd, J = 6.2 and
10.2 Hz, 1H), 5.11–5.36 (m, 4H), 5.43 and 5.49 (2s, 1H), 5.88–6.01
(m, 2H).
Compound 7g
1
Yield: 47%. H-NMR (CDCl3) d: 1.59–1.63 (m, 2H), 1.73–1.75 (m,
2H), 2.80 (s, 3H), 3.03 (s, 1H), 3.38–3.44 (m, 1H), 3.65 (t, J =
11.4 Hz, 2H), 3.81–3.90 (m, 1H), 4.07 (t, J = 11.7 Hz, 2H), 4.45–
4.52 (m, 2H), 4.93–4.98 (m, 1H), 5.18–5.29 (m, 2H), 5.80–5.91
(m, 1H), 7.19–7.31 (m, 9H), 7.44 (d, J = 9.3 Hz, 6H). 13C-NMR
(CDCl3) d: 27.74, 36.08, 41.03, 42.94, 46.38, 49.13, 54.24, 58.45,
64.24, 66.75, 67.76, 116.32, 126.27, 128.52, 129.87, 133.11,
153.43, 170.62.
Compound IIe
1
Yield: 32%. H-NMR (CDCl3) d: 1.22–1.33 (m, 6H), 1.62–1.65 (m,
3H), 2.56–2.67 (m, 2H), 0.03–3.05 (m, 2H), 3.07–3.12 (m, 2H),
3.30–3.42 (m, 1H), 3.71–3.75 (m, 1H), 3.91–4.24 (m, 2H), 4.52-
4.62 (m, 4H), 4.64 (dd, J = 5.4 and 8.8 Hz, 1H), 4.81 (dd, J = 6.0 and
9.7 Hz, 1H), 5.19–5.33 (m, 4H), 5.42 and 5.45 (2s, 1H), 5.85–5.94
(m, 2H).
Allyl (1R,5S,6S)-6-[(1R)-hydroxyethyl]-2-{[5-(5-methyl-
1,1-dioxo-[1,2,5]thiadiazolidin-2-yl)carbonyl]-1-
(allyloxycarbonyl)pyrrolidin-3-ylthio}-1-methylcarbapen-
2-em-3-carboxylate IIa
Compound IIf
1
To a solution of 7a (0.61 g, 1.0 mmol) in CH2Cl2 (2 mL) was added
dropwise triethylsilane (0.20 mL, 1.2 mmol) at 58C, and then TFA
(2). After stirring for 30 min at room temperature, the mixture
was evaporated under reduced pressure.
Yield: 41%. H-NMR (CDCl3) d: 1.24 (d, J = 7.3 Hz, 3H), 1.31 (d, J =
6.2 Hz, 3H), 1.87–2.00 (m, 2H), 2.60–2.71 (m, 2H), 2.96–2.98 (m,
3H), 3.21–3.26 (m, 1H), 3.37–3.47 (m, 2H), 3.60–3.62 (m, 1H),
4.04–4.07 (m, 2H), 4.21–4.25 (m, 2H), 4.52–4.74 (m, 4H), 4.78
(dd, J = 5.4 and 10.3 Hz, 1H), 4.80 (dd, J = 5.6 and 9.8 Hz, 1H),
5.16–5.30 (m, 4H), 5.41 and 5.47 (2s, 1H), 5.89–5.97 (m, 2H).
The residue was dissolved with ethyl acetate and washed with
10% NaHCO3 and brine. The organic layer was concentrated in
vacuo to give a residue Ia, which was used without further purifi-
cation. A solution of 8 (0.40 g, 0.80 mmol) in CH3CN (10 mL) was
cooled to 08C under N2. To this solution was added diisopropyl-
ethyl 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. Evaporation in vacuo gave a
foam, which was purified by silica gel chromatography (EtOAc /
n-hexane = 3 : 1) to give IIa (0.11 g, 29%) as a yellow amorphous
solid.
Compound IIg
1
Yield: 40%. H-NMR (CDCl3) d: 1.26 (d, J = 6.2 Hz, 3H), 1.35 (d, J =
6.8 Hz, 3H), 1.76–1.83 (m, 2H), 1.86–1.98 (m, 1H), 2.90 (s, 3H),
3.24–3.27 (m, 1H), 3.35–3.46 (m, 3H), 3.62–3.69 (m, 2H), 3.86–
3.88 (m, 1H), 4.06–4.13 (m, 2H), 4.15–4.26 (m, 2H), 4.52–4.60
(m, 4H), 4.71 (dd, J = 5.2 and 10.8 Hz, 1H), 4.80 (dd, J = 5.6 and
7.8 Hz, 1H), 5.18–5.34 (m, 4H), 5.41 and 5.47 (2s, 1H), 5.90–5.97
(m, 2H).
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

532
S. J. Kim et al.
Arch. Pharm. Chem. Life Sci. 2009, 342, 528–532
2.56–2.60 (m, 2H), 3.27–3.45 (m, 5H), 3.55–3.62 (m, 2H), 3.71–
3.84 (m, 2H), 4.06–4.14 (m, 5H). IR (KBr): 3470, 3330, 1730, 1710,
1660, 1340 (S=O) cm– 1. HRMS(FAB) calcd. for C17H24N4O7S2:
460.1086. Found: 460.1083.
(1R,5S,6S)-6-[(1R)-Hydroxyethyl]-2-{5-[(5-methyl-1,1-
dioxo-[1,2,5]thiadiazolidin-2-yl)carbonyl]pyrrolidin-3-
ylthio}-1-methylcarbapen-2-em-3-carboxylic acid IIIa
To a stirred solution of IIa (93 mg, 0.13 mol) and Pd(PPh3)4
(10 mg) in CH2Cl2 (5 mL) was added dropwise n-tributytin
hydride (0.13 mL, 0.22 mmol) at 08C and was stirred for 1 h at
same temperature. The resulting solution was diluted with
water (10 mL) and the organic layers were washed with water
(2610 mL). The combined aqueous layers were washed with
ethyl ether (2610 mL) and lyophilized to give a yellow powder
which was purified on a Diaion HP-20 column, eluting with 2%
THF in water. Fractions having UV absorption at 298 nm were
collected and lyophilized again to give the title compound IIIa
as an amorphorus solid.
Compound IIIf
Yield: 17%. UV kmax: 298 nm. 1H-NMR (D2O) d: 1.14 (d, J = 7.0 Hz,
3H), 1.22 (d, J = 6.2 Hz, 3H), 1.59–1.65 (m, 3H), 2.49–2.61 (m, 2H),
3.44–3.27 (m, 8H), 3.71 (m, 2H), 3.90 (bs., 2H), 4.09–4.13 (m, 3H).
IR (KBr): 3450, 3330, 1740, 1710, 1660, 1340 (S=O) cm– 1
HRMS(FAB) calcd. for C18H26N4O7S2: 474.1243. Found: 474.1245.
.
Compound IIIg
1
Yield: 18%. UV kmax: 298 nm. H-NMR (D2O) d: 1.11 (d, J = 6.7 Hz,
3H), 1.18 (d, J = 6.3 Hz, 3H), 1.81 (bs, 1H), 2.03–2.11 (m, 1H),
2.64–2.74 (m, 2H), 2.81 (s, 2H), 3.02–3.05 (m, 1H), 3.21–3.25 (m,
1H), 3.35–3.37 (m, 2H), 3.61–3.71 (m, 3H), 4.01–4.15 (m, 4H). IR
(KBr): 3470, 3350, 1730, 1700, 1640, 1320 (S=O) cm– 1. HRMS(FAB)
calcd. for C19H28N4O7S2: 488.1399. Found: 488.1400.
Compound IIIa
Yield: 18%. UV kmax: 298 nm. 1H-NMR (D2O) d: 1.08 (d, J = 6.4 Hz,
3H), 1.17 (d, J = 5.4 Hz, 3H), 2.34–2.39 (2bs, 1H), 2.58–2.64 (m,
2H), 2.69 (s, 3H), 3.19–3.26 (m, 3H), 3.29–3.39 (m, 4H), 3.54–3.65
(m, 1H), 3.66–3.76 (m, 1H), 3.92–3.86 (m, 3H), 4.08–4.15 (m, 2H).
IR (KBr): 3450, 3330, 1750, 1710, 1680, 1340 (S=O) cm– 1
HRMS(FAB) calcd. for C18H26N4O7S2: 474.1243. Found: 474.1247.
.
The synthesis of compounds IIIb–g was carried out by the
same procedure as described for the preparation of IIIa.
References
[1] W. Leanza, K. Wildonger, T. W. Miller, B. G. Christensen, J.
Med. Chem. 1979, 22, 1435–1436.
Compound IIIb
Yield: 19%. UV kmax: 298 nm. 1H-NMR (D2O) d: 1.10 (s, 3H), 1.12 (d, J
= 4,6 Hz, 3H), 1.29 (d, J = 5.2 Hz, 3H), 1.78–1.90 (m, 1H), 1.98 (bs,
1H), 2.89–2.91 (m, 1H), 3.01–3.09 (m, 2H), 3.18–3.29 (m, 2H),
3.42–3.51(m, 3H), 3.70–3.72 (m, 1H), 3.80–3.85 (m, 1H), 3.87–
4.06 (m, 2H), 4.08–4.19 (m, 5H). IR (KBr): 3470, 3300, 1730, 1710,
1670, 1320 (S=O) cm– 1. HRMS(FAB) calcd. for C19H28N4O7S2:
488.1399. Found: 488.1400.
[2] J. Birnbaum, F. M. Kahan, J. S. MacDonald, Am. J. Med.
1985, 78, (Suppl. 6A), 3–21.
[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] Y. Iso, T. Irie, Y. Nishino, K. Motokawa, Y. Nishitani, J. Anti-
biot. 1996, 49, 199–209.
Compound IIIc
1
[6] K. Inoue, Y. Hamana, T. Inoue, M. Fukasawa, M. Kato,
Abstracts of Papers of 34th Intersci. Conference on Antimi-
crob. Agents Chemother., 1994. No. 1, Orlando.
Yield: 21%. UV kmax: 298 nm. H-NMR (D2O) d: 1.10 (d, J = 4.4 Hz,
3H), 1.21 (d, J = 4.0 Hz, 3H), 1.18(s, 3H), 1.70–2.01 (m, 2H), 2.16–
2.31 (m, 1H), 2.63–2.71 (m, 1H), 2.92–3.16 (m, 2H), 3.30–3.52
(m, 2H), 3.52–3.55 (m, 3H), 3.93–4.00 (m, 2H), 4.09–4.13 (m, 4H).
[7] N. Sato, F. Ohba, Drugs Future 1996, 21, 361–365.
[8] C.-H. Oh, J.-H. Cho, J. Antibiot. 1994, 47, 126–128.
IR (KBr): 3470, 3350, 1750, 1720, 1680, 1340 (S=O) cm– 1
HRMS(FAB) calcd. for C18H26N4O7S2: 474.1243. Found: 474.1244.
.
[9] C. B. Jin, I. S. Jung, H.-J. Ku, J. W. Yook, et al., Toxicology
1999, 138, 59–67.
Compound IIId
[10] C.-H. Oh, H.-W. Cho, I.-K. Lee, J.-Y. Gong, et al., Arch. Pharm.
2002, 335, 152–158.
Yield: 15%. UV kmax: 298 nm. 1H-NMR (D2O) d: 1.11 (d, J = 3.6 Hz,
3H), 1.19 (d, J = 5.7 Hz, 3H), 1.26 (s, 6H), 1.62–1.66 (m, 2H), 2.36–
2.41 (m, 1H), 2.74–2.70 (m, 2H), 3.23–3.34 (m, 6H), 3.53–3.64
(m, 2H), 3.87–3.89 (m, 1H), 4.05–4.15 (m, 2H). IR (KBr): 3500,
3340, 1730, 1710, 1680, 1340 (S=O) cm– 1. HRMS(FAB) calcd. for
C19H28N4O7S2: 488.1399. Found: 488.1401.
[11] C.-H. Oh, H.-G. Dong, H.-W. Cho, S. J. Park, et al., Arch.
Pharm. 2002, 335, 200–206.
[12] C.-H. Oh, H.-W. Cho, J.-H. Cho, Eur. J. Med. Chem. 2002, 37,
743–754.
[13] S.-J. Kim, H. B. Park, J.-H. Cho, C.-H. Oh, Eur. J. Med. Chem.
2007, 42, 1176–1183.
Compound IIIe
1
Yield: 15%. UV kmax: 298 nm. H-NMR (D2O) d: 1.12 (d, J = 6.3 Hz,
[14] D. H. Shih, F. L. Baker, B. G. Christensen, Heterocycles 1984,
21, 29–40.
3H), 1.28 (d, J = 6.0 Hz, 3H), 1.76–1.81 (m, 1H), 2.32–2.37 (m, 1H),
i 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com