Synthesis and antibacterial activity of 1β-methylcarbapenem having a 1,3-diazabicyclo[3.3.0]octan-4-one moiety, Part II

Article abstract of DOI:10.1002/(SICI)1521-4184(19994)332:4<111::AID-ARDP111>3.0.CO;2-W

The synthesis of a new series of 1β-methylcarbapenems having a 1,3- diazabicyclo[3.3.0]octan-4-one moiety is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria are tested and the effect of substituent on the bicyclic ring was investigated. A particular compound (11h) having aminoethyl group showed the most potent antibacterial activity.

Full text of DOI:10.1002/(SICI)1521-4184(19994)332:4<111::AID-ARDP111>3.0.CO;2-W

Full Papers
Synthesis and Antibacterial Activity of 1β-Methylcarbapenem Having a
1,3-Diazabicyclo[3.3.0]octan-4-one Moiety, Part II
a)
b)
a)
a)
c)
a)
d)
Chang-Hyun Oh , Seung Chan Lee , Sung-Jin Park , In-Kyu Lee , Ki Hong Nam , Ki-Soo Lee , Bong-Young Chung ,
a)
Jung-Hyuck Cho *
a) Medicinal Chemistry Research Center, Korea Institute of Science and Technology, Seoul 130-650, Korea
b) Choong Wae Pharmaceutical Co., Seoul 156-010, Korea
c) Dong Kook Pharmaceutical Co., Seoul 135-280, Korea
d) Dept. of Chem. Korea University, Seoul 136-701, Korea
Key Words: Carbapenem; antibacterial activity; substituent effect
Summary
The synthesis of a new series of 1β-methylcarbapenems having a
1,3-diazabicyclo[3.3.0]octan-4-one moiety is described. Their in
vitro antibacterial activities against both Gram-positive and Gram-
negative bacteria are tested and the effect of substituent on the
bicyclic ring was investigated. A particular compound (11h) hav-
ing aminoethyl group showed the most potent antibacterial activ-
ity.
tan-4-one moiety at the C-2 position were synthesized and
their in vitro antibacterial activities were tested.
Preparation of representative 1,3-diazabicyclothiols bear-
ing alkyl, benzyl, 2-aminoethyl moieties at the N-3 position
are shown in Scheme 1. A series of 1,3-diazabicyclothiols
were prepared from commercially available trans-hydroxy-
Introduction
L-proline. N-Protection of 1 was carried out with PNZ-Cl and
subsequent esterification with methanol in the presence of
sulfuric acid gave the N-protected methyl ester (2). Mesyla-
tion of the secondary alcohol withmesyl chloride and triethyl-
amine followed by the treatment with methanolic ammonia
yielded the mesylated amide (4). Deprotection and cycliza-
tion of 4 was achieved through catalytic hydrogenation and
by reaction with acetone to give the bicyclic product (5).
N-Alkylation of the cyclized amide (5) was carried out with
alkyl halide in the presence of sodium hydride. Treatment of
6 with potassium thioacetate in DMF and toluene gave 2,2-
dimethyl-3-alkyl-7-acetylthio-1,3-diazabicylo[3.3.0]octan-
4-one (7). Finally, the acetylthio group of 7 was readily
hydrolyzed with 4N NaOH in methanol to give 1,3-diazabi-
cyclothiol (8).
The discovery of carbapenem, which was isolated from
thienamycin in 1976 as a new family of β-lactam antibiot-
ics, led to a reevaluation of the traditional rules of Structure-
Activity Relationship (SAR) in β-lactam antibiotics.
Imipenem, as a first commercially available synthetic carba-
penem, is highly valued in the clinic for its efficacy against
serious bacterial infections. However, due to its instability to
renal dehydropeptidase-I (DHP-I), it is used in combination
[1]
with cilastatin, a typical DHP-I inhibitor. In 1984, it was
[2]
reported by Merck
that the placement of a methyl group
on the 1β-position of the carbapenem nucleus resulted in a
great improvement of the chemical and metabolic stability.
Since 1β-methylcarbapenems became known, many new
potent carbapenem antibiotics have been reported such as
[3]
[4]
meropenem, biapenem, BO-2727 , and S-4661 . Recently
we developed DK-35C
[5]
Preparation of the 2-(diphenylphosphoryloxy)carbapenem
carbapenem antibiotics, which
[10]
(9) has been reported
. Reaction of 9 with thiol (8) in the
exhibited greater potency compared to imipenem or
meropenem and is now in the preclinical development stage.
However, a number of problems still remain with these
agents, in particular, the relatively weak activity against
resistant bacteria. In order to overcome this problem, most of
the research in our group is currently focussed on finding new
presence of diisopropylethylamine provided the 2-substituted
carbapenem (10). The synthesis of final product (11) was
completed by catalytic hydrogenolysis over 10% Pd/C in
phosphate buffer (pH = 7). Compounds 11a–11h were pre-
pared analogously (Scheme 2).
carbapenem derivatives bearing a bicyclic moiety at the C-
[6,7]
2 position
.
Antibacterial Activity
[8,9]
In preceding papers
we already reported the syntheses
and biological properties of carbapenems having various
The minimum inhibitory concentrations (MICS) of the
substituents at the C-2 position. In this study a series of newly synthesized carbapenem compounds 11a–11h were
1,8-methylcarbapenems having a 1,3-diazabicyclo[3.3.0]oc- determined by an agar dilution method using Mueller-Hinton
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0365-6233/99/0404/0111 $17.50 +.50/0

112
Jung-Hyuck Cho and co-workers
Scheme 1. a: p-nitrobenzylchloroformate, 4N NaOH. b: MeOH, H2SO4: MsCl/CH2Cl2, NEt3. d: NH3/MeOH. e: H2, Pd/C.
f: acetone, reflux. g: RX, NaH/THF. h: CH3COSK/DMF. i: 4N NaOH/MeOH.
Scheme 2
(2S,4R)-4-Hydroxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine-2-carboxylic
Acid Methyl Ester (2)
agar (Table 1). All these compounds showed an excellent
broad spectrum of activity against Gram-positive bacteria.
The effect of the substituent on the bicyclic ring was investi-
gated: the larger the size of the substituent, the lower the
activity against Pseudomonas aeruginosa. Most compounds
showed improved antibacterial activity against the Es-
cherichia coli, Salmonella typhimurium, and Enterobacter
cloacae strains compared to imipenem.
To a solution of trans-hydroxy-L-proline (1, 13.1 g, 10.0 mmol) and
100 ml of 2N NaOH was added dropwise a solution of p-nitrobenzyl chloro-
formate (23.7 g, 11.0 mmol) in CH2Cl2 (20 ml) at 0–5 °C. After stirring for
4 h at the same temperature, 2N NaOH (25 ml) was added. The aqueous
layer, separated from the reaction mixture, was washed with CH2Cl2 (30 ml)
and acidified with H2SO4. The resulting solid was collected by filtration,
washed with cold water, and dried in the atmosphere. To a stirred solution
of the above solid in MeOH (150 ml) was added a small amount of sulfuric
acid at 0 °C and the mixture was refluxed for 3 h. The solution was concen-
trated under reduced pressure, diluted with ethyl acetate and the organic layer
was washed with NaHCO3 solution, water, and brine. Evaporation of the
solvent in vacuo gave an oily liquid which was purified by silica gel column
chromatography to give 2 as a pale yellow oil, yield 26.6 g (82.1%).–
1H-NMR (CDCl3): δ (ppm) = 2.05–2.12 (m, 1H, C3-Ha), 2.35 (in, 1H,
C3-Hb), 2.62 (s, 1H, OH), 3.57 (m, 2H, C5-H), 3.57 and 3.60 (2s, 3H, OCH3),
4.45 (m, 2H, C2, C4-H), 5.13–5.34 (s and 2d, 2H, J = 11.0 Hz), 7.40–7.52
(dd, 2H, Jl = 8.60, J2 = 6.3 Hz), 8.16 (d, 2H, J = 8.60 Hz).– 13C-NMR
(CDCl3): δ (ppm) 171.5, 123.6, 127.9, 66.9, 58.9, 52.0, 30.8, 29.3, 24.8.– MS
m/z 324 (M+ Cl4H16N0O7).
In particular among synthesized compounds, compound
11h, bearing aminoethyl, exhibited the most potent antibac-
terial activity.
Experimental Part
Melting point (mp): Thomas Hoover apparatus, uncorrected. UV spectra:
Hewlett Packard 8451A UV-VIS spectrophotometer. 1H-NMR spectra:
Varian Gemini 300 spectrometer, tetramethylsilane (TMS), as an internal
standard. The mass spectrometry system was based on a HP5989A MS
Engine (Palo Alto, CA, USA) mass spectrometer with a HP Model 59987A
Electrospray MS system. Procedures are given only for compounds 6b–11b,
which exemplify the typical syntheses for the rest of the target molecule.
Arch. Pharm. Pharm. Med. Chem. 332, 111–114 (1999)

1β-Methylcarbapenems
113
Table 1. Antibacterial activities of the carbapenem derivatives.
————————————————————————————————————————————————————
MIC (µg/ml)a
Compound
R
———————————————————————————————
S.p S.a E.c P.a S.t En.c
————————————————————————————————————————————————————
11a
H
0.05
0.02
0.10
0.10
0.02
0.10
0.01
0.01
0.02
0.01
0.40
0.40
0.80
0.80
0.40
0.80
0.40
0.20
0.20
0.01
0.05
0.05
0.10
0.10
0.05
0.05
0.05
0.05
0.03
0.20
6.25
6.25
6.25
25.0
12.5
25.0
100
0.20
0.10
0.40
0.80
0.10
0.05
0.05
0.05
0.10
0.80
0.05
0.05
0.20
0.20
0.05
0.05
0.05
0.05
0.05
0.10
11b
CH3
11c
C2H5
11d
C3H7
11e
allyl
11f
cyclopropyl
benzyl
C2H4NH2
11g
11b
6.25
0.40
1.56
DK-35C
imipenem
—————————————————————————————————————————————————————
a Agar dilution method.s
b S.p: Streptococcus pyogenes 308A, S.a: Staphylococcus aureus 285, E.c: Escherichia coli DC 2, P.a: Pseudomonas aeruginosa 1771,
S.t: Salmonella typhimurium, En.c: Enterobacter cloacae 1321 E.
(2S,4R)-4-Mesyloxy-l-(p-nitrobenzyloxycarbonyl)pyrrolidine-2-carboxylic
Acid Methyl Ester (3)
1H, C3-Hb), 3.12 (s, 3H, mesyl), 3.87 (m, 2H, C5-H), 4.04 (m, 1H, C4-H),
4.55 (m, 1H, C2-H), 7.05 and 7.40 (2s, 2H, CONH2).
A mixture of the above solid and anhydrous Na2SO4 (20 g) in acetone
(100 ml) was refluxed for 8 h. After the solution was filtered, the filtrate was
evaporated under reduced pressure to afford a crude solid, which was washed
with n-hexane to give 5 as a white solid, yield 3.5 g (55.3%).– Mp 142–
143 °C.– 1H-NMR (CDCl3): δ (ppm) = 1.45 and 1.50 (2s, 6H, 2CH3), 2.30
(m, 1H, C6-Ha), 2.56 (m, 1H, C6-Hb), 3.10 (s, 3H, mesyl), 3.87(m, 2H, C8-H),
4.14 (m, 1H, C7-H), 5.25 (m, 1H, C5-H), 6.40 (s, 1H, NH).– 13C-NMR
(CDCl3): δ (ppm) 178.1, 80.2, 62.6, 54.2, 38.8, 33.5, 30.5, 29.7, 23.7.– MS
m/z 248 (M+ C9H16N2O4S).
A solution of 2 (3.17 g, 9.8 mmol) and triethylamine (1.5 g, 15 mmol) in
dry CH2Cl2 was cooled to –5 °C under nitrogen and treated with methane-
sulfonyl chloride (1.5 g, 14.6 mmol). The mixture was stirred at 0 °C for 1 h,
diluted with ethyl acetate (50 ml), and washed with cold water and brine. The
organic layer was dried over anhydrous Na2SO4. Evaporation of the solvent
in vacuo gave a crude solid, which was recrystallized from MeOH/n-hexane
to give 4 as a white solid, yield 3.7 g (97.1%). mp 78.0–80.0 °C.– 1H-NMR
(CDCl3): δ (ppm) = 2.32 (m, 1H, C3-Ha), 2.65 (m, 1H, C3-Hb), 3.12 (s, 3H,
mesyl), 3.67 and 3.78 (2s, 3H, OCH3), 3.87 (m, 2H, C5-H), 4.07 (m, 1H,
C4-H), 4.45 (m, 1H, C2-H), 5.13–5.34 (s and 2d, 2H, J = 11.0 Hz), 7.49–7.59
(dd, 2H, J = 8.60 Hz), 8.19 (d, 2H, J1 = 8.60, J2 = 6.3 Hz).– 13C-NMR
(CDCl3): δ (ppm) 171.5, 153.8, 127.9, 123.5, 65.85, 57.1, 53.4, 37.2, 36.0,
30.8.– MS m/z 402 (M+ C15H18N2O7S1).
(5S,7R)-2,2-Dimethyl-7-mesyloxy-3-methyl-4-oxo-1,3-diazabicyclo[3.3.0]-
octane (6b)
To a solution of NaH (0.3 g, 10.5 mmol) in dry THF (100 ml) at 0 °C was
slowly added a solution of 5 (2 g, 8.1 mmol) in THF under N2 gas. After 1 h
methyl iodide (9.1 g, 32.0 mmol) was added dropwise to the reaction mixture
which was stirred for a further 24 h and then diluted with sat. NH4Cl (30 ml)
and ethyl acetate (50 ml). The organic layer was washed with brine and dried
over anhydrous Na2SO4. Removal of the solvent gave a crude residue, which
was chromatographed on silica gel using ethyl acetate as eluent to give 6b
(2S,4R)-2-Carbamoyl-4-mesyloxy-l-(p-nitrobenzyloxycarbonyl)pyrrolidine
(4)
To a stirred solution of 3 (10.8 g, 26.0 mmol) in MeOH (10 ml) was added
ammonium hydroxide (28%, 30 ml) and and the mixture was stirred for 10 h
at room temperature. The resulting solid was collected by filtration, washed
with cold water, and dried in the atmosphere, yield 5.5 g (55.1%).– Mp
142–144 °C.– 1H-NMR (CDCl3): δ (ppm) = 2.33 (m, 1H, C3-Ha), 2.70 (m,
1H, C3-Hb), 3.12 (s, 3H, mesyl), 3.87 (m, 2H, C5-H), 4.04 (m, 1H, C4-H),
4.55 (m, 1H, C2-H), 5.03–5.32 (s and 2d, 2H, J = 11.0 Hz), 6.90 and 7.10 (2s,
2H, CONH2), 7.49–7.59 (dd, 2H, J = 8.60 Hz), 8.19 (d, 2H, J = 8.60 Hz)
1
as a pale yellow solid, yield 2.05 g (89.1%).– Mp 105–107 °C.– H-NMR
(CDCl3): δ (ppm) = 1.45 and 1.50 (2s, 6H, 2CH3), 2.30 (m, 1H, C6-Ha), 2.56
(m, 1H, C6-Hb), 2.80 (s, 3H, N-CH3), 3.10 (s, 3H, mesyl), 3.87 (m, 2H, C8-H),
4.14 (m, 1H, C7-H), 5.25 (m, 1H, C5-H).– 13C-NMR (CDCl3): δ (ppm) 178.1,
79.9, 61.9, 54.3, 38.8, 34.9, 33.6, 29.7, 27.6, 22.5
(5S,7S)-7-Acetylthio-2,2-dirnethyl-3-methyl-4-oxo-1,3-diazabicyclo[3.3.0]-
octane (7b)
(5S,7R)-2,2-Dimethyl-7-mesyloxy-4-oxo-1,3-diazabicyclo[3.3.0]octane (5)
A mixture of 6b (2 g, 7.2 mmol) and potassium thioacetate (2.9 g,
21.6 mmol) in DMF (30 ml) was stirred at 65 °C for 3 h under N2 gas. After
cooling, the reaction mixture was diluted with ethyl acetate (100 ml), water
(100 ml) and the aqueous layer was washed with ethyl acetate (50 ml × 2).
The combined solvent was washed with brine and dried over anhydrous
Na2SO4. Removal of the solvent gave a crude residue, which was chroma-
A mixture of 4 (10.0 g, 25.8 mmol) and palladium on charcoal (1.0 g) was
dissolved in THF (25 ml) and MeOH (25 ml). The mixture was hydrogenated
at 50 psi for 2 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
purification.– 1H-NMR (CDCl3): δ (ppm) = 2.33 (m, 1H, C3-Ha), 2.70 (m,
Arch. Pharm. Pharm. Med. Chem. 332, 111–114 (1999)

114
Jung-Hyuck Cho and co-workers
11c: 1H-NMR (D2O): δ (ppm) = 1.08 (t, 3H, CH2CH3), 1.30 (s, 3H), 1.35
(s, 3H), 1.38 (d, 3H, 1-CH3, J = 7.2 Hz), 1.49 (d, 3H, CH3CHOH, J = 6.2 Hz),
2.06 (m, 1H, C′6-Ha), 2.20 (s, 1H, OH), 2.56 (m, 1H, C′6-Hb), 3.05 (m, 1H),
3.30 (dq, 1H, C1-H), 3.35 (t, 2H, NCH2CH3) 3.87 (m, 2H, C′8-H), 4.11 (m,
1H, C′7-H), 4.25–4.35 (m, 2H, C5-H and CH3CHOH), 4.45 (t, 1H).
11d: 1H-NMR (D2O): δ (ppm) = 1.04 (t, 3H, NCH2CH2CH3), 1.30 (s, 3H),
1.35 (s, 3H), 1.38 (d, 3H, 1-CH3, J = 7.2 Hz), 1.49 (d, 3H, CH3CHOH,
J = 6.2 Hz), 1.55 (m, 2H), 2.06 (m, 1H, C′6-Ha), 2.20 (s, 1H, OH), 2.56 (m,
1H, C′6-Hb), 3.05 (m, 1H), 3.30 (dq, 1H, C1-H), 3.87 (m, 2H, C′8-H), 4.14
(m, 1H, C′7-H), 4.25–4.35 (m, 2H, C5-H and CH3CHOH), 4.41 (t, 1H).
tographed on silica gel using ethyl acetate/n-hexane (3:1) to give 7b as a pale
yellow oil, yield 1.5 g (84.9%).– 1H-NMR (CDCl3): δ (ppm) = 1.45 and 1.50
(2s, 6H, 2CH3), 2.30 (s, 3H, -SCOCH3), 2.36 (m, 1H, C6-Ha), 2.56 (m, 1H,
C6-Hb), 2.80 (s, 3H, N-CH3), 3.87 (m, 2H, C8-H), 4.14 (m, 1H, C7-H).–
13C-NMR: δ (ppm) 225.4, 178.1, 61.9, 54.3, 41.1, 38.8, 34.9, 33.6, 29.7, 27.6,
22.5.– MS m/z 248 (M+ C11H18N2O2S).
(5S,7S)-2,2-Dimethyl-7-rnercaptan-3-rnethyl-4-oxo-1,3-diazabicyclo-
[3.3.0]octane (8b)
1
To a solution of 7b (1.42 g, 5.8 mmol) in MeOH (15 ml) was added 1.5 ml
of 4N NaOH at ice bath temperature. After stirring for 20 min, 1.5 ml of 4N
HCl was added to this solution, which was then diluted with ethyl acetate,
washed with water and with brine, and dried over anhydrous Na2SO4. The
solvent was evaporated in vacuo to give 8b as a yellow oil, yield 1.15 g
(89.1%).– 1H-NMR (CDCl3): δ (ppm) = 1.45 and 1.50 (2s, 6H, 2CH3), 1.80
(s, 1H, SH), 2.36 (m, 1H, C6-Ha), 2.56 (m, 1H, C6-Hb), 2.80 (s, 3H, N-CH3),
3.87 (m, 2H, C8-H), 4.14 (m, 1H, C7-H).
11e: H-NMR (D2O): δ (ppm) = 1.30 (s, 3H), 1.35 (s, 3H), 1.38 (d, 3H,
1-CH3, J = 7.2 Hz), 1.49 (d, 3H, CH3CHOH, J = 6.2 Hz), 2.06 (m, 1H,
C′6-Ha), 2.20 (s, 1H, OH), 2.56 (m, 1H, C′6-Hb), 2.80 (s, 3H, N-CH3), 3.05
(m, 1H), 3.30 (dq, 1H, Cl-H), 3.87–3.93 (m, 4H, C′8-H and CH2CH=CH2),
4.14 (m, 1H, C′7-H), 4.25–4.35 (m, 2H, C5-H and CH3CHOH), 4.43 (t, 1H),
5.10–5.23 (m, 2H, CH2CH=CH2), 5.80 (m, 1H, CH2CH=CH2).– MS m/z 436
(MH+ C21H29N3O5S).
11f: 1H-NMR (D2O): δ (ppm) = 0.48 (m, 2H), 0.68 (m, 2H), 1.30 (s, 3H),
1.35 (s, 3H), 1.38 (d, 3H, 1-CH3, J = 7.2 Hz), 1.49 (d, 3H, CH3CHOH,
J = 6.2 Hz), 2.06 (m, 1H, C′6-Ha), 2.20 (s, 1H, OH), 2.56 (m, 1H, C′6-Hb),
2.80 (s, 3H, N-CH3), 3.05 (m, 1H), 3.30 (dq, 1H, C1-H), 3.87 (m, 2H, Cδ8-H),
4.14 (m, 1H, C′7-H), 4.25–4.35 (m, 2H, C5-H and CH3CHOH), 4.43 (t, 1H).
p-Nitrobenzyl(1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(5S,7S)-2,2-dimethyl-
3-methyl-4-oxo-1,3-diazabicyclo[3.3.0]octan-7-ylthio)-1-methylcarbapen-
2-em-3-carboxylate (10b)
1
11g: H-NMR (D2O): δ (ppm) = 1.30 (s, 3H), 1.35 (s, 3H), 1.38 (d, 3H,
A solution of p-nitrobenzyl-(1R,5S,6S)-3-(diphenylphosphoryloxy)-
6[(R)-1-hydroxyethyl]-l-methylcarbapen-2-em-3-carboxylate (9, 7.40 g,
12.4 mmol) in CH3CN (50 ml) was cooled to 0 °C under N2. To this solution
was added diisopropylethylamine (2.5 ml, 12.4 mmol) and a solution of the
mercapto compound 8b (2.51 g, 12.4 mmol) in CH3CN (10 ml). After stir-
ring for 2 h, the mixture was diluted with ethyl acetate, washed with 10%
NaHCO3, brine, and dried over MgSO4. Evaporation in vacuo gave a foam
which was purified by silica gel chromatography to give 10b as a yellow
foam solid, yield 4.31 g (60.5%).– 1HMR (CDCl3): δ (ppm) = 1.30 (s, 3H),
1.35 (s, 3H), 1.38 (d, 3H, 1-CH3, J = 7.2 Hz), 1.49 (d, 3H, CH3CHOH,
J = 6.2 Hz), 2.06 (m, 1H, C′6-Ha), 2.20 (s, 1H, OH), 2.56 (m, 1H, C′6-Hb),
2.80 (s, 3H, N-CH3), 3.05 (m, 1H), 3.30 (dq, 1H, C1-H), 3.87 (m, 2H, C′8-H),
4.14 (m, 1H, C′7-H), 4.25–4.35 (m, 2H, C5-H and CH3CHOH), 4.33 (t, 1H),
5.13–5.34 (s and 2d, 2H, J = 11.0 Hz), 7.80 (d, 2H, J = 8.67 Hz), 8.16 (d, 2H,
J = 8.67 Hz).
1-CH3, J = 7.2 Hz), 1.49 (d, 3H, CH3CHOH, J = 6.2 Hz), 2.06 (m, 1H,
C′6-Ha), 2.20 (s, 1H, OH), 2.56 (m, 1H, C′6-Hb), 2.80 (s, 3H, N-CH3), 3.05
(m, 1H), 3.30 (dq, 1H, C1-H), 3.87 (m, 2H, C′8-H), 4.14 (m, 1H, C′7-H),
4.25–4.35 (m, 2H, C5-H and CH3CHOH), 4.43 (t, 1H), 5.7 (dd, 2H), 7.50
(bs, 5H).– MS m/z 472 (MH+ C24H29N3O5S).
11h: 1H-NMR (D2O): δ (ppm) = 1.30 (s, 3H), 1.35 (s, 3H), 1.38 (d, 3H,
1-CH3, J = 7.2 Hz), 1.49 (d, 3H, CH3CHOH, J = 6.2 Hz), 2.06 (m, 1H,
C′6-Ha), 2.20 (s, 1H, OH), 2.56 (m, 1H, C′6-Hb), 2.80 (s, 3H, N-CH3), 3.05
(m, 1H), 3.20 (t, 2H, CH2CH2NH2) 3.30 (dq, 1H, C1-H), 3.34 (t, 2H,
CH2CH2NH2) 3.87 (m, 2H, C′8-H), 4.14 (m, 1H, C′7-H), 4.25–4.35 (m, 2H,
C5-H and CH3CHOH), 4.43 (t, 1H).
Reference
[1] D.B.R. Johnston, S.M. Schmitt, B.G. Christensen, J. Am. Chem. Soc.
1978, 100, 313–315.
(1R,5S,6S)-6-[(1R)-1-Hydroxyethyl]-2-[(5S, 7S)-2,2-dimethyl-3-methyl-
4-oxo-1,3-diazabicyclo[3.3.0]octan-7-ylthio)-1-methylcarbapen-2-em-
3-carboxylic Acid (11b)
[2] D.H. Shih, F. Baker, L. Cama, B.G. Christensen, Heterocycles 1984,
21, 29–40.
[3] E. Yamail, T. Watanabe, I. Nakayama, 35th Interscience Conference
on Antimicroblal Agents and Chemotherapy, San Francisco, Califor-
nia, USA, September 17–20, 1995, Abstract F 141.
Compound 10b (0.10 g, 0.17 mmol) and 0.1 g of Pd/C (10%) were dis-
solved in THF/phosphate buffer (pH = 7) (1:1, 10 ml each). The mixture was
hydrogenated at 50 psi 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 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 11b as a white powder, yield 20 mg (26.3%).– 1H-NMR
(D2O): δ (ppm) = 1.30 (s, 3H), 1.35 (s, 3H), 1.38 (d, 3H, 1-CH3, J = 7.2 Hz),
1.49 (d, 3H, CH3CHOH, J = 6.2 Hz), 2.06 (m, 1H, C′6-Ha), 2.20 (s, 1H, OH),
2.56 (m, 1H, C′6-Hb), 2.80 (s, 3H, N-CH3), 3.05 (m, 1H), 3.30 (dq, 1H, C1-H),
3.87 (m, 2H, C′8-H), 4.14 (m, 1H, C′7-H), 4.25–4.35 (m, 2H, C5-H and
CH3CHOH), 4.43 (t, 1H).– MS m/z 410 (MH+ C19H27N3O5S).
Compound 11a–11h were prepared by same procedure as described for the
preparation of 11b.
[4] S. Arakawa, S. Kamidono, T. Inamatsu, J. Shimada, 37th Interscience
Conference on Antimicrobial Agents and Chemotherapy, Toronto,
Ontario, Canada, September 28–October 1, 1970, Abstract F 218.
[5] C.-H. Oh, J.-H. Cho, J. Antibiotics 1994, 47, 126–128.
[6] C.-H. Oh, Y.H. Ham, J.-H. Cho, Arch Pharm. (Weinheim) 1995, 328,
289–291.
[7] C.-H. Oh, H.J. Kim, J.-H. Cho, Arch Pharm. (Weinheim) 1995, 328,
385–387.
[8] K.-H. Nam, C.-H. Oh, J.K. Cho, K.-S. Lee, J.-H. Cho, Arch Pharm.
Pharm. Med. Chem. 1996, 329, 289–291.
[9] K.-H. Nam, C.-H. Oh, Y.H. Ham, K.-S. Lee, J.-H. Cho, Arch Pharm.
Pharm. Med. Chem. 1997, 330, 268–270.
11a:1H-NMR (D2O): δ (ppm) = 1.25 (s, 3H), 1.32 (s, 3H), 1.35 (d, 3H,
1-C113, J = 7.2 Hz), 1.45 (d, 3H, CH3CHOH, J = 6.2 Hz), 2.04 (m, 1H,
C′6-Ha), 2.46 (m, 1H, C′6-Hb), 3.05 (m, IH), 3.33 (dq, 1H, C1-H), 3.87 (m,
2H, C′8-H), 4.10 (m, 1H, C′7-H), 4.25–4.35 (m, 2H, C5-H and CH3CHOH),
4.43 (t, 1H).
[10] T. Kametani, K. Fukumoto, M. Ihara, Heterocycles 1980, 14, 1305–
1311
Received: September 22, 1998 [FP333]
Arch. Pharm. Pharm. Med. Chem. 332, 111–114 (1999)