Synthesis and antibacterial activity of 1beta-methylcarbapenems having a 2, 2-disubstituted-1, 3-diazabicyclo[3.3.0]octan-4-one moiety and related compounds. Part III.

Article abstract of DOI:10.1002/1521-4184(200205)335:5<200::AID-ARDP200>3.0.CO;2-X

The synthesis of new series of 1beta-methylcarbapenems having a 2, 2-disubstituted-1, 3-diazabicyclo[3.3.0]octan- and -[4.3.0]nonan-4-one moiety is described.Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of the substituent of the bicyclic ring was investigated. A particular compound (16 f) bearing a hydroxymethyl group showed the most potent antibacterial activity and the compound (17 a) with a 1, 3-diazabicyclo[4.3.0]nonane moiety exhibited excellent stability against renal dehydropeptidase-I (DHP-I) to Meropenem.

Full text of DOI:10.1002/1521-4184(200205)335:5<200::AID-ARDP200>3.0.CO;2-X

200 Oh et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 5, 200–206
Chang-Hyun Oha,
Hyun-Gu Donga,
Han-Won Choa,
Sung Jin Parka,
Joon Hee Hongb,
Daejin Baekc,
Synthesis and Antibacterial Activity of
1␤-Methylcarbapenems Having a
2,2-disubstituted-1,3-Diazabicyclo[3.3.0]octan-4-one
Moiety and Related Compounds. Part III
Jung-Hyuck Choa
The synthesis of new series of 1β-methylcarbapenems having a 2,2-disubstituted-
1,3-diazabicyclo[3.3.0]octan- and -[4.3.0]nonan-4-one moiety is described.Their in
vitro antibacterial activities against both Gram-positive and Gram-negative bacteria
were tested and the effect of the substituent of the bicyclic ring was investigated. A
particular compound (16 f) bearing a hydroxymethyl group showed the most potent
antibacterial activity and the compound (17 a) with a 1,3-diazabicyclo[4.3.0]nonane
moiety exhibited excellent stability against renal dehydropeptidase-I (DHP-I) to
Meropenem.
a
Medicinal Chemistry
Research Center,
Korea Institute of Science
and Technology, Seoul,
Korea
College of Pharmacy,
Chosun University, Kwangju,
Korea
b
c
Department of Chemistry,
Keywords: Carbapenem; Antibacterial activity; Substituent effect
Hanseo University,
Seosan, Korea
Received: November 21, 2001 [FP648]
carbapenem C-2 position were synthesized and their in
vitro antibacterial activities were tested.
Introduction
In 1984, it was reported by Merck [1] that the introduction
of a methyl group at the 1β-position of the carbapenem
nucleus resulted in a great improvement of the com-
pound’s chemical and metabolic stability.Once 1β-meth-
ylcarbapenem was known, many new potent carbapen-
em antibiotics have been reported such as meropenem,
biapenem, BO-2727 [2], and S-4661 [3].Recently we de-
veloped DK-35C carbapenem antibiotics [4], which ex-
hibited better potency compared to imipenem or mero-
penem and is now in the preclinical development stage.
However, a number of problems still remain with these
agents, in particular, their relatively weak activity against
resistant bacteria. In order to overcome this drawback,
we have tried to synthesize novel carbapenem deriva-
tives bearing a heterocyclic and bicyclic moiety at their
C-2 position [5–8].
Chemistry
The synthetic route leading to 1,3-diazabicyclo[3.3.0]-
octan-4-one-7-thiols bearing an alkyl, phenyl, vinyl, or
hydroxyl group at the C-2 position of the bicyclic ring is
shown in Scheme 1. In the preceding paper [9], we re-
ported the synthetic route to the amide compound (1)
from trans-hydroxy-L-proline. The bicyclic product (2)
could be formed by sequential catalytic hydrogenation
and cyclization with the ketone derivative in the pres-
ence of acid catalyst.Treatment of 2 with potassium thio-
acetate in DMF and toluene co-solvent system gave 2,2-
disubstituted-7-acetylthio-1,3-diazabicyclo[3.3.0]octan-
4-ones (3) as diastereomeric mixtures, which were read-
ily separated by silica gel column chromatography using
EtOAc/hexane (3 : 1) as eluent. Due to difficulties in sep-
aration, compounds 3 c and 3 e could only be obtained
as diastereomeric mixture. Finally, the acetylthio group
of 3 was readily hydrolyzed with 4N NaOH in methanol to
give 2,2-disubstituted 1,3-diazabicyclothiol (4).
In the preceding paper [9], we reported the synthesis
and antibacterial activity of carbapenem compounds
having an N-substituted 1,3-diazabicyclo[3.3.0]octan-4-
one moiety at the C-2 position. In order to find new carb-
apenems which posses good antibacterial activity
against Gram-positive and Gram-negative bacteria and
high stability to renal dehydropeptidase-I (DHP-I), we
studied the modification of a substituent on the 1,3-
diazabicyclo[3.3.0]octan- and -[4.3.0]nonan-4-one thiol
moiety.In this work, some new carbapenems having 2,2-
disubstituted-1,3-diazabicyclo[3.3.0]octan-4-one at the
Correspondence: Jung-Hyuck Cho, Medicinal Chemistry
Research Center, Korea Institute of Science and Technology,
Seoul 130-650, Korea, Fax: +82
choh@kist.re.kr.
The synthetic route to 2,2-disubstituted-1,3-diazabi-
cyclo[4.3.0]nonane derivatives (12a-b) is shown in
2 958 5189, e-mail:
© WILEY-VCH Verlag GmbH, 69451 Weinheim, 2002
0365-6233/05/0200 $ 17.50+.50/0

Arch. Pharm. Pharm. Med. Chem. 2002, 335, 200–206
Synthesis and Antibacterial Activity 201
Scheme 1
Scheme 2. The ester derivative (5) was easily prepared
from trans-hydroxy-L-proline using well-known meth-
ods.Compound 5 was reduced with calcium borohydride
in EtOH and was O-mesylated with mesyl chloride to
give 6.The mesylate (6) was converted into the cyanide
compound (7) with sodium cyanide in DMSO. Com-
pound 7 was hydrolyzed to the corresponding amide (8)
with sulfuric acid in THF solvent. Also, the bicyclic prod-
uct (9) was readily obtained through the catalytic hydro-
genation and acid catalyzed cyclization with the ketone
derivative. Debenzoylation of compound 9 with potassi-
um hydroxide gave the hydroxyl derivative, which was
converted into the O-mesylate (10) by treatment with
mesyl chloride. Preparation of thiols (12 a–b) from 10
was carried out by a similar method to the preparation of
4 a.
Reaction of 13 with thiols (4 a–h, 12 a–b) in the presence
of diisopropylethylamine provided the 2-substituted
Scheme 2

202 Oh et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 200–206
Scheme 3
Table 1. In vitro antibacterial activity (MIC, µg/ml) and DHP-I stability of the carbapenem derivatives
STRAINS
16 a 16 aЈ 16 b 16 bЈ 16 ca 16 d 16 ea 16 f 16 g 16 h 17 a 17 b Imi- Mero-
penem penem
1
2
3
4
5
6
7
8
9
Streptococcus pyogenes 308A
Streptococcus pyogenes 77A
Staphylococcus aureus SG511
Staphylococcus aureus 285
Escherichia coli DC2
0.02 0.02 0.02 0.01 0.01 0.02 0.01 0.05 0.02 0.01 0.01 0.01 < 0.01
0.01
0.05 0.02 0.02 0.01 0.01 0.02 0.01 0.03 0.02 0.01 0.01 0.01 < 0.01 < 0.01
0.05 0.05 0.10 0.05 0.10 0.20 0.10 0.05 0.20 0.20 0.20 0.20
0.10 0.05 0.10 0.02 0.10 0.05 0.20 0.05 0.40 0.10 0.80 0.40
0.05 0.03 0.03 0.03 0.05 0.05 0.20 0.05 0.10 0.10 0.10 0.40
0.10 0.10 0.10 0.05 0.05 0.10 0.10 0.20 0.10 0.20 0.10 0.40
0.01
0.01
0.40
0.20
0.80
0.80
0.10
0.10
1.79
0.10
0.10
0.03
0.03
0.20
0.03
0.05
0.03
9.69
Eschrichia coli TEM
Pseudomonas aeruginosa 1592E 6.25 6.25 6.25 6.25 3.15 3.15 25.0 1.56 1.56 1.56 25.0 6.25
Salmonella typhimurium
0.20 0.40 0.20 0.80 0.40 0.40 0.20 0.10 0.20 0.20 0.10 0.20
0.05 0.20 0.05 0.10 0.20 0.20 0.80 0.10 0.40 0.20 0.20 0.20
0.05 0.20 0.05 0.20 0.10 0.20 0.40 0.10 0.10 0.10 0.10 0.10
13.81 12.14 14.75 14.07 11.23 11.91 15.92 13.58 11.50 9.40 21.85 18.33
Klebsiella aerogenes 1522E
10 Enterobacter cloacae 1321E
DHP-1
a
diastereomeric mixture
carbapenem (14 a–h, 15 a–b) as shown in Scheme 3.
Deprotection of these compounds by catalytic hydrogen-
ation gave the crude products, which were purified by re-
versed phase column chromatography to give the pure
carbapenems.
ism was investigated for 2ЈR (16 aЈ, 16 bЈ) and 2ЈS (16 a,
16 b) isomers. The 2ЈR isomers exhibit higher activities
against Gram-positive bacteria than that of the 2ЈS iso-
mers, but lower activities for Gram-negative bacteria.
Compared to the I and II series, the compounds 16 g and
16 h, with 5-5 fused ring system show greater activity to-
wards Gram-positive bacteria and Gram-negative bac-
teria than compounds 17 a and 17 b, which posses a 5–6
fused ring system. Among the compounds 16, most
showed improved antibacterial activity against Es-
cherichia coli, Salmonella typhimurium, and Entero-
bacter cloacae strains compared to imipenem. Of these
compounds, 16 f, having a hydroxy methyl group, exhibit-
ed the most potent antibacterial activity. The stability to
Antibacterial activity
The minimum inhibitory concentrations (MICs) of the
carbapenem compounds (16 a–h, 17 a–b) were deter-
mined by an agar dilution method using Mueller-Hinton
agar (Table 1).The effects of bicyclic ring substituent on
antiviral activities were investigated:the larger the size of
the substituent, the lower the activity towards Pseu-
domonas aeruginosa. Also, the effect of stereoisomer-

Arch. Pharm. Pharm. Med. Chem. 2002, 335, 200–206
Synthesis and Antibacterial Activity 203
under N2 gas. After cooling, the reaction mixture was diluted
with EtOAc (50 mL), water (20 mL) and the aqueous layer was
washed with EtOAc (20 mL × 2). The combined organic layers
were washed with H2O, brine and dried over anhydrous
Na2SO4. Removal of the solvent gave a crude residue, which
was purified by silica gel column chromatography with EtOAc/
hexane (3 : 1) to give 3 a (0.65 g, 70.5 %, S-isomer) and 3 aЈ
DHP-I of all compounds tested exceeded that of Mero-
penem; in particular, compound 17 a and 17 b exhibited
the greatest stability.
Experimental part
Melting point (mp): Thomas Hoover apparatus, uncorrected.
UV spectra: Hewlett Packard 8451A UV-VIS spectrophotome-
ter.1H NMR spectra:Varian Gemini 300 spectrometer, tetrame-
thylsilane (TMS), as an internal standard. Structures of the
stereoisomers were identified on the basis of the NOESY spec-
trum recorded with a UNITY plus-300 and a Gemini Varian 300
NMR spectrometer.The mass spectrometry system was based
on a HP5989A MS Engine (Palo Alto, CA, USA). IR spectra:
Perkin Elmer 16F-PC FT-IR. Optical rotations were determined
using an Autopol III automatic polarimeter.
1
(0.20 g, 21.7 %, R-isomer) as a pale yellow oil. 3 a; H NMR
(CDCl3):δ (ppm) = 0.91 (t, 3 H, J = 7.3 Hz), 1.36 (s, 3 H), 1.69 (q,
2 H, J = 7.3 Hz), 1.97 (m, 1 H), 2.30 (s, 3 H), 2.50–2.61 (m, 2 H),
3.25 (t, 1 H, J = 6.3 Hz), 3.95 (m, 2 H), 7.25 (s, 1 H); 13C NMR: δ
(ppm) = 195.7, 178.4, 78.4, 63.9, 54.3, 40.1, 36.1, 32.5, 31.0,
20.7, 9.4. – 3 aЈ; 1H NMR (CDCl3): δ (ppm) = 0.91 (t, 3 H, J =
7.3 Hz), 1.35 (s, 3 H), 1.71 (q, 2 H, J = 7.3 Hz), 2.05 (m, 1 H),
2.31 (s, 3 H), 2.5–2.61 (m, 2 H), 3.25 (t, 1 H, J = 6.3 Hz), 4.01
(m, 2 H), 6.31 (s, 1 H); 13C NMR: δ (ppm) = 195.4, 178.1, 76.9,
61.1, 54.3, 41.1, 36.8, 32.5, 30.6, 21.1, 9.9.
Measurement of in vitro antibacterial activity
Compounds 3 b–h were prepared from 2 b–h using a method
similar to that described for the preparation of 3 a.
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/mL with the same broth and inoc-
ulated with an inoculating device onto agar containing serial
twofold dilutions of the test compounds. Organisms were incu-
bated at 37 °C for 18–20 h.The MIC of a compound was defined
as the lowest concentration that visibly inhibited growth.
3 b:Yield 58.5 %. [α]D20 = –20.01 (0.5, CHCl3); 1H NMR (CDCl3):
δ (ppm) = 0.92 (t, 3 H, J = 7.2 Hz), 1.28–1.34 (m, 2 H), 1.37 (s,
3 H), 1.61 (q, 2 H, J = 7.2 Hz), 1.87 (m, 1 H), 2.32 (s, 3 H), 2.50–
2.64 (m, 2 H), 3.25 (t, 1 H, J = 6.4 Hz), 3.95 (m, 2 H), 7.62 (s,
1 H);IR (KBr):3340 (NH), 1720, 1660 cm–1;13C NMR:δ (ppm) =
195.7, 178.5, 78.1, 63.7, 54.0, 45.9, 40,3, 32.5, 30.9, 21.3,
18.3, 14.6.
Determination of susceptibility to renal dehydropeptidase-I
(DHP-I)
3 bЈ:Yield 13.3 %.[α]D20 = –34.95 (0.5, CHCl3);1H NMR (CDCl3):
δ (ppm) = 0.91 (t, 3 H, J = 7.3 Hz), 1.21–1.29 (m, 2 H), 1.36 (s,
3 H), 1.69 (q, 2 H, J = 7.3 Hz), 1.97 (m, 1 H), 2.30 (s, 3 H), 2.59
(m, 2 H), 3.25 (m, 1 H), 4.10 (m, 2 H), 6.31 (s, 1 H). IR (KBr):
3340 (NH), 1720, 1660 cm–1. 13C NMR: δ (ppm) = 195.6, 178.4,
78.1, 63.6, 52.9, 45.9, 40.2, 39.5, 31.5, 27.0, 18.3, 14.9.
The relative hydrolysis rate of carbapenems by porcine renal
DHP-I was determined, taking the initial hydrolysis rate of imi-
penem as 1.0. Partially purified porcine DHP-I (final concentra-
tion, 0.3 U/mL) was incubated with 50 µM carbapenem at 35 °C
in 50 mM MOPS buffer, pH 7.0. The initial hydrolysis rate was
monitored by the spectrophotometric method.One unit of activ-
ity was defined as the amount of enzyme hydrolyzing 1 µM of
glycyldehydrophenylalanine per min when the substrate,
50 µM, was incubated at 35 °C in 50 mM MOPS buffer, pH 7.0.
3 c (mixture):Yield 59.2 %. 1H NMR (CDCl3):δ (ppm) = 0.40 (m,
1 H), 0.56 (m, 2 H), 1.05 (m, 1 H), 1.31 (s, 3 H), 1.55 (m, 1 H),
1.87 (m, 1 H), 2.32 (s, 3 H), 2.51–2.63 (m, 2 H), 3.25 (m, 1 H),
3.81–3.97 (m, 2 H), 8.01 (s, 1 H); IR (KBr): 3340 (NH), 1740,
1690 cm–1.
(2R/S,5S,7R)-2-Ethyl-2-methyl-7-mesyloxy-4-oxo-1,3-diaza-
bicyclo[3.3.0]octane (2 a)
3 d:Yield 76.1 %. [α]D20 = –27.5 (0.5, CHCl3); 1H NMR (CDCl3): δ
(ppm) = 1.29 (s, 3 H), 1.88 (m, 1 H), 2.32 (s, 3 H), 2.52–2.64 (m,
1 H), 2.88 (m, 1 H), 3.31 (t, 1 H, J = 5.7 Hz), 3.81–4,02 (m, 2 H),
5.51 (br s, 1 H), 6.16 (s, 1 H), 6.38 (d, 1 H, J = 9.1 Hz), 7.51 (s,
1 H); IR (KBr): 3390 (NH), 1720, 1660 cm–1.
A mixture of 1 (2.0 g, 5.17 mmol) and palladium on charcoal
(1.0 g) was dissolved in THF (30 mL) and MeOH (30 mL). The
mixture was hydrogenated at 310 kPa for 1 h and was filtered
through celite. The filtrate was concentrated in vacuo to give a
crude solid, which was used in the following step without further
purification. A mixture of the above solid and anhydrous
Na2SO4 (10 g) in 2-butanone (20 mL) and CH3CN (20 mL) was
refluxed for 6 h. After the reaction mixture was filtered, the fil-
trate was evaporated under reduced pressure to afford a crude
residue, which was purified by silica gel column chromatogra-
phy to give a diastereomeric mixture 2 a as a pale yellow oil,
yield 1.06 g (78.0 %); 1H NMR (CDCl3): δ (ppm) = 0.91 (t, 3 H,
J = 7.3 Hz), 1.35 (s, 3 H), 1.68 (q, 2 H, J = 7.3 Hz), 2.00 (m,
1 H), 2.56 (m, 2 H), 3.10 (s, 3 H), 3.28 (m, 1 H), 4.10 (m, 2 H),
6.39 (s, 1 H); 13C NMR (CDCl3): δ (ppm) = 178.1, 80.2, 77.1,
62.6, 54.2, 38.8, 33.5, 30.5, 29.7, 23.7.
3 dЈ:Yield 4.3 %.[α]D20 = –51.15 (0.5, CHCl3);1H NMR (CDCl3):δ
(ppm) = 1.31 (s, 3 H), 1.89 (m, 1 H), 2.32 (s, 3 H), 2.51–2.61 (m,
1 H), 2.88 (m, 1 H), 3.31 (t, 1 H, J = 5.7 Hz), 3.81–4.02 (m, 2 H),
5.22 (br s, 1 H), 6.15 (s, 1 H), 6.78 (d, 1 H, J = 9.1 Hz), 7.41 (s,
1 H); IR (KBr): 3370 (NH), 1710, 1700 cm–1.
3 e (mixture):Yield 59.9 %. 1H NMR (CDCl3): δ (ppm) = 1.32 (s,
3 H), 1.90 (m, 1 H), 2.31 (s, 3 H), 2.51–2.66 (m, 2 H), 3.25 (t,
1 H, J = 6.4 Hz ), 3.89–3.99 (m, 2 H), 7.43 (t, 2 H, J = 7.4 Hz),
7.56 (t, 1 H, J = 7.4 Hz), 7.65 (br s, 1 H), 8.01 (d, 2 H, J = 7.4 Hz);
IR (KBr): 3340 (NH), 1730, 1690 cm–1.
3 f:Yield 89.3 %.[α]D20 = –19.91 (0.5, CHCl3);1H NMR (CDCl3):δ
(ppm) = 1.26 (s, 3 H), 1.97 (m, 1 H), 2.30 (s, 3 H), 2.69 (t, 2 H, J =
6.9 Hz ), 3.20 (m, 1 H), 3.50 (t, 2 H, J = 6.1 Hz), 3.86 (m, 1 H),
3.95 (m, 1 H), 7.55 (s, 1 H); IR (KBr): 3520 (OH), 3350 (NH),
1710, 1690 cm–1.
Compounds 2 b–h were similarly prepared from 1 with the cor-
responding ketones according to the procedure described for
2 a.
(2R/S,5S,7S)-7-Acetylthio-2-ethyl-2-methyl-4-oxo-1,3-
diazabicyclo[3.3.0]octane (3 a)
3 g:Yield 87.4 %.1H NMR (CDCl3):δ (ppm) = 0.92 (t, 3 H, J = 7.4
Hz), 0.99 (t, 3 H, J = 7.4 Hz), 1.69–1.75 (br s, 4 H), 1.90 (m, 1 H),
2.33 (s, 3 H), 2.59–2.74 (m, 2 H), 3.25 (br s, 1 H), 3.98 (m, 2 H),
7.05 (br s, 1 H); IR (KBr): 3340 (NH), 1730, 1680 cm–1.
A mixture of 2 a (1.0 g, 3.8 mmol) and potassium thioacetate
(2.0 g, 17.6 mmol) in DMF (30 mL) was stirred at 65 °C for 3 h

204 Oh et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 200–206
3 h:Yield 90.1 %. 1H NMR (CDCl3): δ (ppm) = 1.36 (s, 3 H), 1.45
(s, 3 H), 2.05 (m, 1 H), 2.33 (s, 3 H), 2.59 (m, 1 H), 3.10 (m, 1 H),
3.25 (m, 1 H), 4.04 (m, 2 H), 6.87 (br s, 1 H); IR (KBr): 3350
(NH), 1710, 1690 cm–1.
2 H), 7.42 (m, 4 H), 7.56 (m, 1 H), 7.98 (d, 2 H, J = 7.3 Hz), 8.16
(d, 2 H, J = 8.3 Hz; IR (KBr): 2242 (CN), 1718 (C=O) cm–1; 13
C
NMR (CDCl3): 166, 155, 144, 134, 130, 129, 128, 127, 124,
117, 73, 66, 54, 37, 23.
(2S,5S,7S)-2-Ethyl-2-methyl-7-mercaptan-4-oxo-1,3-diaza-
bicyclo[3.3.0]octane (4 a)
(2S,4R)-4-Benzoyloxy-2-carbamoylmethyl-1-(p-nitrobenzyl-
oxycarbonyl)pyrrolidine (8)
To a solution of 3 a (0.85 g, 3.5 mmol) in MeOH (15 mL) was
added 0.9 mL of 4N-NaOH at ice bath temperature. After stir-
ring for 20 min, 0.9 mL of 4N-HCl was added to this solution and
diluted with EtOAc, washed with water and brine, and dried
over anhydrous Na2SO4.The solvent was evaporated in vacuo
to give 4 a as a yellow oil, yield 0.60 g (95.0 %); 1H NMR
(CDCl3):δ (ppm) = 0.93 (t, 3 H, J = 7.3 Hz), 1.46 (s, 3 H), 1.71 (q,
2 H, J = 7.3 Hz), 2.05 (m, 1 H), 2.66 (m, 2 H), 3.25 (m, 1 H), 4.15
(m, 2 H), 6.78 (s, 1 H); IR (KBr): 3340 (NH), 2540 (SH), 1710,
1670 cm–1.
To a solution of 7 (2.9 g, 7.3 mmol) in THF (20 mL) was added
slowly 3 mL of conc. sulfuric acid, and then it was stirred for 3 h
at 0 °C. The mixture was neutralized with 2N NaOH, and then
diluted with ethyl acetate (50 mL), and washed with cold water
and brine.The organic layer was dried over anhydrous Na2SO4,
which was purified by silica gel column chromatography to give
8 as a pale yellow solid.Yield 92.1 %. Mp 142–145 °C; 1H NMR
(CDCl3): δ (ppm) = 2.19 (m, 1 H), 2.39 (br s, 1 H), 2.75 (m, 2 H),
3.08 (br s, 1 H), 3.87 (d, 2 H, J = 11.2 Hz), 4.33 (m, 1 H), 5.16 (q,
2 H), 5.99–6.30 (d, 2 H, J = 13.9 Hz), 7.40 (m, 4 H), 7.56 (m,
1 H), 7.95 (d, 2 H, J = 7.3 Hz), 8.12 (d, 2 H, J = 8.3 Hz);IR (KBr):
3400 (NH2), 1692 (C=O) cm–1;13C NMR (CDCl3):176, 166, 155,
144, 134, 130, 129, 128, 127, 124, 117, 73, 66, 55, 39, 22.
(2R,5S,7S)-2-Ethyl-2-methyl-7-mercaptan-4-oxo-1,3-diazabi-
cyclo[3.3.0]octane (4 aЈ)
Preparation of compound 4 aЈ from 3 aЈ were carried out by the
same procedure as described for the preparation of 4 a. Yield
92.0 %.1H NMR (CDCl3):δ (ppm) = 0.91 (t, 3 H, J = 7.3 Hz), 1.43
(s, 3 H), 1.70 (q, 2 H, J = 7.3 Hz), 2.01 (m, 1 H), 2.66 (m, 2 H),
3.25 (m, 1 H), 4.15 (m, 2 H), 7.1 (s, 1 H); IR (KBr): 3350 (NH),
2550 (SH), 1710, 1690, 900 cm–1.
(6S,8R)-8-Benzoyloxy-2,2-dimethyl-4-oxo-1,3-diazabicyclo-
[4.3.0]nonane (9 a)
A mixture of 8 (2.0 g, 5.2 mmol) and palladium on charcoal
(1.0 g) was dissolved in THF (30 mL) and MeOH (30 mL).The
mixture was hydrogenated at 310 kPa for 1 h and was filtered
through celite. The filtrate was concentrated in vacuo to give a
crude solid, which was used in the following step without purifi-
cation. A mixture of the above solid and anhydrous Na2SO4
(10.0 g) in acetone (30 mL) was refluxed for 10 h.After the solu-
tion was filtered, the filtrate was evaporated under reduced
pressure to afford a crude residue, which was purified by silica
gel column chromatography to give 9 a as a pale yellow oil.Yield
0.69 g (50.9 %); 1H NMR (CDCl3): δ (ppm) = 1.36 (s, 3 H), 1.41
(s, 3 H), 2.09 (m, 1 H), 2.48 (m, 2 H), 2.78 (d, 1 H, J = 8.5 Hz),
3.08 (d, 1 H, J = 3.1 Hz), 3.57 (br s, 1 H), 3.78 (m, 1 H), 5.33 (m,
1 H), 6.45 (br s, 1 H), 7.42 (m, 2 H), 7.56 (m, 1 H), 8.03 (d, 2 H, J
= 8.3 Hz); IR (KBr): 3435 (NH), 2990, 1716, 1690 (C=O) cm–1;
13C NMR (CDCl3): 171, 167, 135, 134, 130, 129, 73, 69, 52, 51,
39, 37, 29, 22.
Compounds 4 b–h were prepared from 3 b–h by a procedure
similar to that described for the preparation of 4 a.
(2S,4R)-4-Benzoyloxy-2-mesyloxymethyl-1-(p-nitrobenzyl-
oxycarbonyl)pyrrolidine (6)
A solution of NaBH4 (0.54 g 14.3 mmol) in dry EtOH (15 mL)
was added to a solution of powdered CaCl2 (0.94 g, 5.16 mmol)
in dry EtOH (80 mL) at EtOAc –20 °C.The reaction mixture was
stirred for 20 h at –10 °C, and was then added a solution of 5 in
EtOH. After 5 h, the mixture was diluted with H2O (20 mL), 1N-
HCl, and EtOAc (50 mL). The organic layer was dried over an-
hydrous Na2SO4, which was used in the following step without
purification.
A solution of above hydroxyl compound (1.3 g, 2.7 mmol) and
triethylamine (0.57 mL, 4.07 mmol) in dry CH2Cl2 was cooled to
–5 °C under nitrogen and treated with mesyl chloride (0.38 mL,
4.07 mmol).The mixture was stirred at 0 °C for 1 h, diluted with
EtOAc (50 mL), and washed with cold water and brine.The or-
ganic layer was dried over anhydrous Na2SO4, which was puri-
fied by silica gel column chromatography to give 6 as a pale yel-
low oil.Yield 66.9 %. 1H NMR (CDCl3): δ (ppm) = 1.88 (m, 1 H),
2.05 (m, 1 H), 2.80 (m, 3 H), 3.01 (s, 3 H), 3.87 (m, 1 H), 4.33 (m,
2 H), 5.16 (q, 2 H), 7.52 (m, 3 H), 7.46 (d, 2 H, J = 8.3 Hz), 8.06
(d, 2 H, J = 7.3 Hz), 8.16 (d, 2 H, J = 8.3 Hz); IR (KBr): 1718
(C=O) 1182 (S=O) cm–1.
(6S,8R)-8-Benzoyloxy-2,2-diethyl-4-oxo-1,3-diazabicyclo-
[4.3.0]nonane (9 b)
Compound 9 b was prepared from 8 using 2-butanone as de-
scribed for the preparation of 9 a.
Yield 52.2 %. 1H NMR (CDCl3): δ (ppm) = 0.99 (t, 3 H, J =
7.0 Hz), 1.06 (t, 3 H, J = 7.0 Hz), 1.64–1.72 (br s, 4 H), 2.02 (m,
1 H), 2.43 (m, 2 H), 2.78 (d, 1 H, J = 8.6 Hz), 3.08 (d, 1 H, J =
3.1 Hz), 3.61 (br s, 1 H), 3.78 (m, 1 H), 5.33 (m, 1 H), 6.88 (br s,
1 H), 7.42 (m, 2 H), 7.56 (m, 1 H), 8.03 (d, 2 H, J = 8.3 Hz); IR
(KBr): 3450 (NH), 2990, 1720, 1690 (C=O) cm–1.
(2S,4R)-4-Benzoyloxy-2-cyanomethyl-1-(p-nitrobenzyloxy-
(6S,8R)-2,2-Dimethyl-8-mesyloxy-4-oxo-1,3-diazabicyclo-
carbonyl)pyrrolidine (7)
[4.3.0]nonane (10 a)
A mixture of 6 (4.3 g, 9.3 mmol) and sodium cyanide (0.9 g,
18.0 mmol) in DMSO (20 mL) was stirred at 80 °C for 6 h under
N2 gas. After cooling, the reaction mixture was diluted with
EtOAc (50 mL), water (50 mL), and the aqueous layer was
washed with ethyl EtOAc (20 mL × 2). The combined solvent
was washed with brine and dried over anhydrous Na2SO4. Re-
moval of the solvent gave a crude residue, which was separat-
ed by silica gel column chromatography using EtOAc/hexane
(1 : 2) to give 7 as a pale yellow solid. Yield 82.0 %. Mp 98–
100 °C;1H NMR (CDCl3):δ (ppm) = 2.19 (m, 2 H), 2.75 (m, 1 H),
3.08 (m, 2 H), 3.87 (d, 2 H, J = 11.2 Hz), 4.33 (m, 1 H), 5.16 (q,
To a solution of 9 a (0.9 g, 1.7 mmol) in MeOH (20 mL) was add-
ed slowly a solution of potassium hydroxide (2.49 mL,
2.49 mmol) in MeOH, and then it was stirred for 2 h at room
temperature. The mixture was neutralized with 6N HCl, and
then the solvent was concentrated in vacuo to give a residue,
which was used without further purification.A solution of above
solid (0.7 g, 1.6 mmol) and triethylamine (0.23 mL, 1.73 mmol)
in dry CH2Cl2 was cooled to –5 °C under nitrogen and treated
with methanesulfonyl chloride (0.20 g, 1.73 mmol).The mixture
was stirred at 0 °C for 1 h, diluted with EtOAc (50 mL), and
washed with cold water and brine.The organic layer was dried

Arch. Pharm. Pharm. Med. Chem. 2002, 335, 200–206
Synthesis and Antibacterial Activity 205
10 % NaHCO3, brine, and dried over anhydrous MgSO4. Evap-
oration in vacuo gave a foam, which was purified by silica gel
chromatography to give 14 a as a yellow foam solid.Yield 0.86 g
(60.5 %); 1H NMR (CDCl3): δ (ppm) = 0.91 (t, 3 H, J = 7.2 Hz),
1.30 (s, 3 H), 1.35 (d, 3 H, J = 7.0 Hz), 1.39 (d, 3 H, J = 6.2 Hz),
1.75 (q, 2 H, J = 7.2 Hz), 2.01 (m, 1 H), 2.56 (m, 1 H), 3.19-3.35
(m, 2H), 3.87 (m, 2 H), 4.14 (m, 1 H), 4.25–4.41 (m, 3 H), 5.13–
5.34 (s and 2 d, 2 H, J = 11.0 Hz), 7.10 (s, 1 H), 7.80 (d, 2 H, J =
8.6 Hz), 8.16 (d, 2 H, J = 8.6 Hz).
over anhydrous Na2SO4, and was purified by silica gel column
chromatography to give 10 a as a pale yellow oil. Yield 0.60 g
1
(95.0 %); H NMR (CDCl3): δ (ppm) = 1.52 (s, 6 H), 1.99 (m,
1 H), 2.48 (m, 2 H), 2.78 (d, 1 H, J = 8.5 Hz), 3.01 (s, 3 H), 3.08
(d, 1 H, J = 3.1 Hz), 3.57 (br s, 1 H), 4.10 (m, 1 H), 5.20 (m, 1 H),
6.45 (br s, 1 H); IR (KBr): 3410 (NH), 1715 (C=O), 1331 and
1114 (S=O) cm–1.
(6S,8R)-2,2-Diethyl-8-mesyloxy-4-oxo-1,3-diazabicyclo-
[4.3.0]nonane (10 b)
Compounds 14 b–h were prepared from 4 b–h by a similar
manner to that described for the preparation of 14 a.
10 b was prepared from 9 b using a similar method to that de-
scribed for the preparation of 10 a.
(1R,5S,6S)-6-[(1R)-1-Hydroxyethyl]-2-[(2S,5S,7S)-2-ethyl-2-
methyl-3-methyl-4-oxo-1,3-diazabicyclo[3.3.0]octan-7-ylthio]-
1-methyl-1-carbapen-2-em-3-carboxylic acid (16 a)
Yield 92.4 %. 1H NMR (CDCl3): δ (ppm) = 0.95 (t, 3 H, J = 7.0
Hz), 1.01 (t, 3 H, J = 7.0 Hz), 1.67–1.79 (br s, 4 H), 1.99 (m, 1 H),
2.45 (m, 2 H), 2.78 (d, 1 H, J = 8.2 Hz), 3.01 (s, 3 H), 3.08 (d, 1 H,
J = 3.4 Hz), 3.53 (br s, 1 H), 4.10 (m, 1 H), 5.20 (m, 1 H), 6.33 (br
s, 1 H);IR (KBr):3410 (NH), 1720 (C=O), 1330 and 1110 (S=O)
cm–1.
Compound 14 a (0.3 g, 0.5 mmol) and 0.15 g of Pd/C (10 %)
were taken up in THF/phosphate buffer (pH = 7) (1 : 1, 10 mL
each). The mixture was hydrogenated at 345 kPa for 1 h. The
solution was filtered through celite and washed with water (2 ×
10 mL).The combined filtrate was washed with ethyl ether (2 ×
20 mL) and lyophilized to give a yellow powder which was puri-
fied on a reversed-phase column, eluting with 5 %THF in water.
Fractions having UV absorption at 298.2 nm were collected
and lyophilized again to give the title compound 16a as a white
powder. Yield 60 mg (26.3 %). Mp 122–127 °C (dec); 1H NMR
(D2O): δ (ppm) = 0.93 (t, 3 H, J = 7.2 Hz), 1.28 (d, 3 H, J =
7.0 Hz), 1.35 (d, 3 H, J = 6.2 Hz), 1.39 (s, 3 H), 1.81 (q, 2 H, J =
7.2 Hz), 2.01 (m, 1 H), 2.56 (m, 1 H), 3.19–3.35 (m, 2 H), 3.87
(m, 2 H), 4.14 (m, 1 H), 4.25–4.41 (m, 3 H);IR (KBr):3510 (OH),
3350 (NH), 1705, 1680, 1660 (C=O) cm–1; FABMS: m/z 410
(M + H)+.
(6S,8S)-8-Acetylthio-2,2-dimethyl-4-oxo-1,3-diazabicyclo-
[4.3.0]nonane (11 a)
Compound 11 a from 10 a was prepared using a similar method
1
to that described for the preparation of 3 a. Yield 78.0 %. H
NMR (CDCl3): δ (ppm) = 1.62 (s, 6 H), 1.89 (m, 1 H), 2.30 (s,
3 H), 2.48–2.70 (m, 3 H), 3.08 (m, 1 H), 3.17 (m, 1 H), 3.42 (m,
1 H), 4.20 (br s, 1 H); IR (KBr): 3340 (NH), 1707, 1676 (C=O)
cm–1.
(6S,8S)-8-Acetylthio-2,2-diethyl-4-oxo-1,3-diazabicyclo-
[4.3.0]nonane (11 b)
Compound 11 b from 10 b was prepared using a similar meth-
od to that described for the preparation of 4 a.Yield 73.8 %. 1H
NMR (CDCl3): δ (ppm) = 0.97 (t, 3H, J = 7.2 Hz), 1.01 (t, 3H, J =
7.2 Hz), 1.68–61.78 (br s, 4 H), 1.97 (m, 1 H), 2.31 (s, 3 H),
2.43–2.72 (m, 3 H), 3.03 (m, 1 H), 3.17 (m, 1 H), 3.41 (m, 1 H),
4.23 (br s, 1 H); IR (KBr): 3340 (NH), 1707, 1676 (C=O) cm–1.
(1R,5S,6S)-6-[(1R)-1-Hydroxyethyl]-2-[(2R,5S,7S)-2-ethyl-2-
methyl-3-methyl-4-oxo-1,3-diazabicyclo[3.3.0]octan-7-ylthio]-
1-methyl-1-carbapen-2-em-3-carboxylic acid (16 aЈ)
Compound 16 aЈ was prepared by the same procedure as de-
scribed for 16 a.
(6S,8S)-2,2-Dimethyl-8-mercaptan-4-oxo-1,3-diazabicyclo-
[4.3.0]nonane (12 a)
1
Yield 32.1 %; m.p. 132–136 °C (dec); UV λmax: 298.8 nm; H
NMR (D2O): δ (ppm) = 0.91 (t, 3 H, J = 7.2 Hz), 1.23 (d, 3 H, J =
7.0 Hz), 1.29 (d, 3 H, J = 6.0 Hz), 1.35 (s, 3 H), 1.87 (q, 2 H, J =
7.2 Hz), 1.99 (m, 1 H), 2.49 (m, 1 H), 3.21–3.36 (m, 2 H), 3.87
(m, 2 H), 4.14 (m, 1 H), 4.25–4.39 (m, 3 H);IR (KBr):3510 (OH),
3350 (NH), 1705, 1680, 1660 (C=O) cm–1; FABMS m/z 410
(M + H)+.
12 a was prepared from 11 a using a similar method to that de-
scribed for the preparation of 4 a.Yield 1.01 g (91.5 %);1H NMR
(CDCl3): δ (ppm) = 1.62 (s, 6 H), 1.81 (m, 1 H), 1.86 (s, 1 H),
2.58–2.71 (m, 3 H), 3.08 (m, 1 H), 3.17 (m, 1 H), 3.42 (m, 1 H),
4.20 (br s, 1 H); IR (KBr): 3430 (NH), 1676 (C=O) cm–1.
(6S,8S)-2,2-Diethyl-8-mercaptan-4-oxo-1,3-diazabicyclo-
[4.3.0]nonane (12 b)
Compounds 16 b–h were prepared as described for the prepa-
ration of 16 a
16 b:Yield 33.3 %.Mp 125–129 °C (dec);UV λmax:297.8 nm;1H
NMR (D2O): δ (ppm) = 0.91 (t, 3 H, J = 7.2 Hz), 1.25–1.30 (m,
2 H),1.32 (d, 3 H, J = 6.2 Hz), 1.36 (d, 3 H, J = 6.8 Hz), 1.40 (s,
3 H), 1.61 (q, 2 H, J = 7.2 Hz), 1.87 (m, 1 H), 2.50–2.64 (m, 2 H),
3.25–3.45 (m, 3 H), 3.95 (m, 2 H), 4.19–4.31 (m, 2 H); IR (KBr):
3490 (OH), 3350 (NH), 1710, 1680, 1660 (C=O) cm–1; FABMS
m/z 424 (M + H)+.
12 b was prepared from 11 b using a similar method to that de-
scribed for the preparation of 4 a. Yield 90.1 %. 1H NMR
(CDCl3): δ (ppm) = 0.99 (t, 3 H, J = 7.2 Hz), 1.04 (t, 3 H, J = 7.2
Hz), 1.68–1.78 (br s, 4 H), 1.81 (m, 1 H), 1.86 (s, 1 H), 2.58–
2.71 (m, 3 H), 3.08 (m, 1 H), 3.17 (m, 1 H), 3.42 (m, 1 H), 4.20
(br s, 1 H); IR (KBr): 3450 (NH), 1675 (C=O) cm–1.
p-Nitrobenzyl(1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-
[(2S,5S,7S)-2-ethyl-2-methyl-4-oxo-1,3-diazabicyclo[3.3.0]-
octan-7-ylthio]-1-methyl-1-carbapen-2-em-3-carboxylate
(14 a)
16 bЈ:Yield 29.3 %. Mp 150–157 °C (dec); UV λmax: 298.1 nm;
1H NMR (D2O):δ (ppm) = 0.90 (t, 3 H, J = 6.8 Hz), 1.28–1.34 (m,
5 H), 1.37 (d, 3 H, J = 6.8 Hz), 1.40 (s, 3 H), 1.63 (q, 2 H, J = 6.8
Hz), 1.85 (m, 1 H), 2.50–2.65 (m, 2 H), 3.23–3.40 (m, 3 H), 3.95
(m, 2 H), 4.19–4.31 (m, 2 H); IR (KBr): 3490 (OH), 3350 (NH),
1710, 1680, 1660 (C=O) cm–1; FABMS m/z 424 (M + H)+.
A solution of p-nitrobenzyl-(1R,5S,6S)-3-(diphenylphosphor-
yloxy)-6-[(R )-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-
carboxylate (13, 1.48 g, 2.48 mmol) in CH3CN (20 mL) was
cooled to 0 °C under N2.To this solution was added diisopropyl
ethylamine (0.5 mL, 2.48 mmol) and a solution of the mercapto
compound 4 a (0.52 g, 2.48 mmol) in CH3CN (10 mL).After stir-
ring for 4 h, the mixture was diluted with EtOAc, washed with
16 c (mixture):Yield 34.7 %. UV λmax: 296.9 nm; 1H NMR (D2O):
δ (ppm) = 0.44 (m, 1 H), 0.56 (m, 2 H), 1.05 (m, 1 H), 1.22 (d,
3 H, J = 6.9 Hz), 1.28 (d, 3 H, J = 6.0 Hz), 1.34 (s, 3 H), 1.52 (m,
1 H), 1.87 (m, 1 H), 2.51–2.65 (m, 2 H), 3.29–3.56 (m, 3 H),

206 Oh et al.
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 200–206
(d, 3 H, J = 6.2 Hz), 1.64–1.78 (br s, 4 H), 2.02 (m, 1 H), 2.33–
2.53 (m, 3 H), 3.03 (m, 1 H), 3.33 (dq, 1 H, J = 7.2 Hz), 3.87–
3.90 (m, 2 H), 4.11 (m, 1 H), 4.25–4.38 (m, 2 H), 5.11–5.36 (s
and 2 d, 2 H, J = 11.0 Hz), 7.81 (d, 2 H, J = 8.5 Hz), 8.18 (d, 2 H,
J = 8.5 Hz).
3.81–4.01 (m, 2 H), 4.12–4.34 (m, 2 H); IR (KBr): 3490 (OH),
3350 (NH), 1720, 1690, 1670 (C=O) cm–1; FABMS m/z 422
(M + H)+.
16 d: Yield 24.9 %. UV λmax: 298.0 nm. Mp > 161 °C (dec). 1H
NMR (D2O): δ (ppm) = 1.26 (d, 3 H, J = 6.9 Hz), 1.31 (d, 3 H, J =
6.5 Hz), 1.35 (s, 3 H), 1.88 (m, 1 H), 2.42–2.54 (m, 1 H), 2.88
(m, 1 H), 3.31–3.55 (m, 3 H), 3.81–4,02 (m, 2 H), 4.22–4.54 (m,
3 H), 5.55 (m, 1 H), 6.38 (d, 1 H, J = 9.1 Hz); IR (KBr): 3520
(OH), 3340 (NH), 1710, 1670, 1660 (C=O) cm–1; FABMS m/z
408 (M + H)+.
(1R,5S,6S)-6-[(1R)-1-Hydroxyethyl]-2-[(6S,8S)-2,2-dimethyl-
4-oxo-1,3-diazabicyclo[4.3.0]nonan-8-ylthio]-1-methyl-1-car-
bapen-2-em-3-carboxylic acid (17 a)
Compound 17 a was prepared from 15 a by the same proce-
dure as described for the preparation of 16 a.Yield 36.7 %. UV
λ
max:298.9 nm;mp 144–150 °C (dec);1H NMR (D2O):δ (ppm) =
The data of 16 dЈ cannot determined due to the extremely small
amount produced.
1.33 (s, 3 H), 1.38–1.43 (s and d, 6 H), 1.46 (d, 3 H, J = 6.2 Hz),
2.02 (m, 1 H), 2.33–2.51 (m, 3 H), 3.05 (m, 1 H), 3.33 (dq, 1 H, J
= 7.2 Hz), 3.94 (m, 2 H), 4.18–4.35 (m, 4 H); IR (KBr): 3490
(OH), 3350 (NH), 1705, 1690, 1660 (C=O) cm–1; FABMS m/z
410 (M + H)+.
16 e (mixture):Yield 34.1 %.UV λmax:298.8 nm.Mp 141–149 °C
(dec).1H NMR (D2O):δ (ppm) = 1.22 (d, 3 H, J = 6.9 Hz), 1.29 (d,
3 H, J = 6.0 Hz), 1.32 (s, 3 H), 1.90 (m, 1 H), 2.61–2.78 (m, 2 H),
3.28–3.48 (m, 3 H), 3.89–3.99 (m, 2 H), 4.15–4.28 (m, 2 H),
7.41 (t, 2 H, J = 7.2 Hz), 7.56 (t, 1 H, J = 7.2 Hz), 8.11 (d, 2 H, J =
7.2 Hz); IR (KBr): 3490 (OH), 3350 (NH), 2990, 1715, 1680,
1670 (C=O) cm–1; FABMS m/z 458 (M + H)+.
The preparation of 17 b was carried out by a procedure similar
to that described for 16 a
17 b:Yield 33.7 %.UV λmax:298.5 nm;1H NMR (D2O):δ (ppm) =
0.98 (t, 3 H, J = 7.2 Hz), 1.06 (t, 3 H, J = 7.4 Hz), 1.22 (d, 3 H, J =
7.0 Hz), 1.30 (d, 3 H, J = 6.0 Hz), 1.69–1.75 (br s, 4 H), 2.05 (m,
1 H), 2.33–2.46 (m, 2 H), 2.59–2.74 (m, 2 H), 3.25–3.40 (m,
3 H), 3.98 (m, 2 H), 4.15–4.33(m, 2 H); IR (KBr): 3490 (OH),
3350 (NH), 1710, 1680, 1660 (C=O) cm–1; FABMS m/z 438
(M + H)+.
16 f:Yield 34.7 %. UV λmax: 298.4 nm; 1H NMR (D2O): δ (ppm) =
1.23 (d, 3 H, J = 7.0 Hz), 1.31 (d, 3 H, J = 6.1 Hz), 1.34 (s, 3 H),
2.01 (m, 1 H), 2.69 (t, 2 H, J = 6.9 Hz), 3.20 (m, 1 H), 3.30–3.56
(m, 4 H), 3.86 (m, 1 H), 3.95 (m, 1 H), 4.11–4.30 (m, 2 H); IR
(KBr): 3550 (OH), 3330 (NH), 1720, 1685, 1670 (C=O) cm–1;
FABMS m/z 412 (M + H)+.
16 g:Yield 34.7 %. UV λmax: 298.3 nm. Mp 131–136 °C (dec); 1H
NMR (D2O): δ (ppm) = 0.92 (t, 3 H, J = 7.4 Hz), 0.99 (t, 3 H, J =
7.4 Hz), 1.26 (d, 3 H, J = 6.9 Hz), 1.31 (d, 3 H, J = 6.0 Hz), 1.69–
1.75 (br s, 4 H), 2.05 (m, 1 H), 2.59–2.74 (m, 2 H), 3.25–3.40
(m, 3 H), 3.98 (m, 2 H), 4.15–4.33 (m, 2 H);IR (KBr):3480 (OH),
3380 (NH), 1710, 1680, 1660 (C=O) cm–1; FABMS m/z 424
(M + H)+.
16 h:Yield 34.7 %.UV λmax:298.3 nm.Mp 149–155 °C (dec.);1H
References
NMR (D2O): δ (ppm) = 1.23 (d, 3
H, J = 6.9 Hz), 1.28 (d,
[1] D. H. Shih, F. L Baker, B. G. Christensen, Heterocycles
1984, 21, 29–40.
3 H, J = 6.0 Hz), 1.36 (s, 3H), 1.45 (s, 3 H), 2.05 (m, 1 H), 2.58
(m, 1 H), 3.10 (m, 1 H), 3.25–3.51 (m, 3 H), 4.04 (m, 2 H), 4.23–
4.42 (m, 2 H); IR (KBr): 3490 (OH), 3400 (NH), 1710, 1680,
1660 (C=O) cm–1; FABMS m/z 396 (M + H)+.
[2] E. Yamaji, T. Watanabe, I. Nakayama, 35th Interscience
Conference on Antimicrobial Agents and Chemotherapy,
San Francisco, California, USA, September, 1995, 17–20
Abstract F 141.
p-Nitrobenzyl(1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(6S,8S)-
2,2-dimethyl-4-oxo-1,3-diazabicyclo[4.3.0]nonan-8-ylthio]-1-
methyl-1-carbapen-2-em-3-carboxylate (15 a)
[3] S. Arakawa, S. Kamidono, T. Inamatsu, J. Shimada, 37th
Interscience Conference on Antimicrobial Agents and
Chemotherapy, Toronto, Ontario, Canada, September
28–October 1, 1970, Abstact F 218.
Compound 15 a was prepared by the same procedure as
described for the preparation of 14 a.
Yield 60.5 %. 1H NMR (CDCl3): δ (ppm) = 1.30 (s, 3 H), 1.33 (s,
3 H), 1.38 (d, 3 H, J = 7.2 Hz), 1.46 (d, 3 H, J = 6.2 Hz), 2.06 (m,
1 H), 2.36–2.59 (m, 3 H), 3.05 (m, 1 H), 3.30 (dq, 1 H, J = 7.2
Hz), 3.87 (m, 2 H), 4.14 (m, 1 H), 4.25–4.35 (m, 2 H), 5.13–5.34
(s and 2 d, 2 H, J = 11.0 Hz), 7.80 (d, 2 H, J = 8.6 Hz), 8.16 (d,
2 H, J = 8.6 Hz).
[4] C.-H. Oh, J.-H. Cho, J. Antibiotics 1994, 47, 126–128.
[5] C.-H. Oh, Y. H. Ham, J.-H. Cho, Arch. Pharm. (Weinheim)
1995, 328, 289–291.
[6] C.-H. Oh, H. J. Kim, J.-H. Cho, Arch. Pharm. (Weinheim)
1995, 328, 385–387.
p-Nitrobenzyl(1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(6S,8S)-
2,2-diethyl-4-oxo-1,3-diazabicyclo[4.3.0]nonan-8-ylthio]-1-
methyl-1-carbapen-2-em-3-carboxylate (15 b)
[7] K.-H. Nam, C.-H. Oh, J. K. Cho, K.-S. Lee, J.-H. Cho, Arch.
Pharm. Pharm. Med. Chem. 1996, 329, 289–291.
Compound 15 b was prepared by the same procedure as de-
scribed for the preparation of 14 a.
[8] K.-H.Nam, C.-H.Oh,Y.H.Ham, K.-S.Lee, J.-H.Cho, Arch.
Pharm. Pharm. Med. Chem. 1997, 330, 268–270.
Yield 59.9 %. 1H NMR (CDCl3): δ (ppm) = 0.96 (t, 3 H, J =
7.4 Hz), 1.01 (t, 3 H, J = 7.4 Hz), 1.38 (d, 3 H, J = 7.2 Hz), 1.46
[9] C.-H. Oh, S. C. Lee, S.-J. Park, I.-K. Lee, J.-H. Cho, Arch.
Pharm. Pharm. Med. Chem. 1999, 332, 111–114.