Synthesis and antibacterial activities or new carbapenems having a proline reverse amide moiety at the C-2 position

Article abstract of DOI:10.1002/(SICI)1521-4184(199804)331:4<139::AID-ARDP139>3.0.CO;2-U

The synthesis of new 1β-methylcarbapenems (1a-l) having a proline reverse amide moiety at the C-2 position and their in vitro antibacterial activities are described. The compounds were evaluated by the Mueller-Hinton agar dilution method and compared with meropenem as control. Aliphatic amides (1a-h) are found to show greater antibacterial activity than aromatic amides (1i-l). Moreover, C-2 free amino compound (1m) reveals greater activity than any other amide compounds (1a-l).

Full text of DOI:10.1002/(SICI)1521-4184(199804)331:4<139::AID-ARDP139>3.0.CO;2-U

New Carbapenems
139
Synthesis and Antibacterial Activities of New Carbapenems Having
a Proline Reverse Amide Moiety at the C-2 Position
a)
a)
a)
a)
a)
Soon Ho Hwang , Kye Jung Shin , Yong Koo Kang , Dong Jin Kim , Dong Chan Kim ,
a)
a)
b)
Kyung Ho Yoo , Sang Woo Park *, and Kee Jung Lee
a) Medicinal Chemistry Research Center, Korea Institute of Science and Technology, P. O. Box 131, Cheongryang, Seoul 130-650, Korea
b) Department of Industrial Chemistry, Hanyang University, Seoul 133-791, Korea
Key Words 1-β-Methylcarbapenems; proline reverse amide moiety; antibacterial activities
Summary
The synthesis of new 1β-methylcarbapenems (1a–l) having a
proline reverse amide moiety at the C-2 position and their in vitro
antibacterial activities are described. The compounds were evalu-
ated by the Mueller-Hinton agar dilution method and compared
with meropenem as control. Aliphatic amides (1a–h) are found to
show greater antibacterial activity than aromatic amides (1i–l).
Moreover, C-2 free amino compound (1m) reveals greater activity
than any other amide compounds (1a–l).
Scheme 1. Synthesis of 4-mercapto proline reverse amide.
Introduction
i) (PhO)2PON3, N-methylmorpholine; ii) p-methoxybenzyl alcohol,
N-methylmorpholine; iii) CF3CO2H; iv) R-CO2H, DCC, DMAP;
v) 2N NaOH.
[1]
Since the discovery of thienamycin and the appearance
of bacteria resistant to penicillins and cephalosphorins, car-
bapenem antibiotics have become an important class of β-lac-
Synthesis
tam antibiotics. In particular, 1-β-methylcarbapenem deriv-
[2,3]
atives
exhibited an excellent spectrum of activity and
The synthesis of 4-mercaptoproline reverse amides (8a–l)
is described in Scheme 1. N-p-Nitrobenzyloxycarbonyl pro-
tected 4-thioacetyl proline (3) was prepared from trans-4-hy-
droxy-L-proline by a known procedure reported by Suna-
strong stability against renal dehydropeptidase-I (DHP-I).
Recently, Sumitomo developed a 1-β-methyl substituted car-
bapenem with 5′-dimethylaminocarbonyl pyrrolidine-3′-yl
thio group at the C-2 side chain of the carbapenem ring
system, meropenem, which showed a broad and balanced
activity against Gram-positive and Gram-negative bacte-
ria . Thus, our early efforts have been directed toward the
synthesis of new 1-β-methylcarbapenems and the elucidation
of structure activity relationships. Herein we wish to report
the synthesis of the new carbapenems (1a–l) having a proline
reverse amide moiety at the C-2 position and in vitro antibac-
terial activities of those compounds (Fig. 1).
[4]
gawa . Isocyanate 4 was obtained by Curtius rearrange-
[6]
ment with retention of stereochemistry at the proline C-2
[4]
[5]
position of 3, using diphenylphosphoryl azide and N-methyl-
morpholine in benzene at 80 °C in moderate yield (68%).
Scheme 2. Synthesis of 4-mercapto proline amine.
As any attempts to obtain the key intermediate, amine 6,
from isocyanate 4 directly failed, isocyanate 4 was treated
with p-methoxybenzyl alcohol toaffordthep-methoxybenzyl
carbamate 5 as a protected amine compound, which was
further transformed to the amine trifluoroacetic acid by the
treatment with trifluoroacetic acid. Amidation of amine 6
with various aliphatic and aromatic acids in DCC and DMAP
gave 4-thioacetyl reverse amides; subsequent saponification
with aqueous 2N NaOH in MeOH gave 4-mercapto proline
reverse amides (8a–l). 4-Mercapto proline amine (8m) for the
synthesis of C-2 free amino carbapenem (1m) was prepared
from isocyanate 4 according to Scheme 2.
Fig. 1. New carbapenems having a proline reverse amide moiety.
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0365-6233/98/0404/0139 $17.50 +.50/0

140
Park and co-workers
Table 1. In vitro antibacterial activities of carbapenems 1a–m (MIC, µg/ml).
——————————————————————————————
Organism
1a
1b
1c
1d
1e
1f
1g
——————————————————————————————
S. p. 77A
S. f. MD8b
S. a. SG511
S. a. 285
0.02 0.01 0.01 0.2
12.5 12.5 12.5 50
0.1
25
0.1
25
0.8
50
0.2
0.4
0.1
0.2
0.1
0.2
0.2
0.1
0.2
1.5
1.5
0.4
0.8
0.8
0.8
1.5
0.4
0.2
0.4
0.8
0.8
6.2
6.2
6.2
3.1
6.2
100
100
12.5
25
E. c. O55
E. c. DC2
E. c. TEM
P. a. 9027
P. a. 1771
S. t.
0.05 0.05 1.5
0.1
0.1
0.1
0.1
1.5
3.1
12.5 50
12.5 100
100
12.5 25
6.2
0.4
0.2
0.4
0.1
12.5 6.2
6.2
1.5
1.5
0.8
0.8
6.2
1.5
1.5
0.4
0.4
Scheme 3. Synthesis of new carbapenems.
0.2
0.2
0.2
0.2
0.4
0.2
3.1
6.2
6.2
K. o. 1082E
E. c. P99
E. c. 1321E
There was a tendency toward greater antibacterial activity
of aliphatic amides (1a–h) than those of aromatic amides
(1i–l) and the bulkier the size of amide, the lower the activity
against Gram-positive and Gram-negative bacteria. Interest-
ingly, C-2 free amino compound (1m) showed greater activ-
ity than any other amide compounds (1a–l). However, all the
compounds synthesized showed poor activities against both
Gram-positive and Gram-negative bacteria compared with
meropenem, particularly against Pseudomonas aeruginosa.
Thus we could infer from the above results that the introduc-
tion of reverse amide to the proline C-2 position instead of
carboxamides was not desirable for improving the antibacte-
rial activities.
12.5
6.2
0.05 0.05 1.5
——————————————————————————————
Organism 1h 1i 1j 1k 1l 1m MPM
——————————————————————————————
S. p. 77A
S. f. MD8b
S. a. SG511
S. a. 285
0.2
50
0.1
50
0.2
50
0.4
50
0.05 0.01 <0.002
12.5 12.5 12.5
1.5
1.5
1.5
0.8
3.1
100
100
3.1
6.2
3.1
1.5
0.8
0.8
0.8
1.5
0.8
50
1.5
1.5
1.5
1.5
1.5
100
100
3.1
6.2
3.1
1.5
0.8
1.5
1.5
1.5
3.1
100
100
3.1
0.4
0.4
0.4
0.8
0.4
0.1
0.1
0.1
0.2
0.1
0.1
0.2
E. c. O55
E. c. DC2
E. c. TEM
P. a. 9027
P. a. 1771
S. t.
0.01
0.03
0.03
0.2
Acknowledgments
12.5 1.5
12.5 3.1
We are grateful to the Ministry of Science and Technology (MOST) of
Korea for financial support, and wish also to thank Il-Dong Pharm. Co. for
its donation of Chair Fund to KIST.
50
0.2
1.5
3.1
1.5
0.8
0.8
0.2
0.4
0.1
0.1
0.03
0.05
0.03
0.03
K. o. 1082E
E. c. P99
E. c. 1321E
12.5 0.8
Experimental Section
6.2
1.5
0.8
0.4
Melting points Thomas-Hoover apparatus (uncorrected).– UV spectra
Hewlett Packard 8451A UV-VIS spectrophotometer.– IR spectra Perkin-El-
mer 1710 spectrophotometer, KBr discs.– 1H NMR spectra Varian Gemini
300 spectrometer, TMS int. standard.– MS data Hewlett Packard 59987A
electrospray-5989A mass spectrometer.
——————————————————————————————
Abbreviations: S. p. Streptococcus pyogenes, S. f. Streptococcus faecium, S.
a. Staphylococcus aureus, E. c. Escherichia coli, P. a. Pseudomonas aerugi-
nosa, S. t. Salmonella typhimurium, K. o. Klebsiella oxytoca, E. c. Entero-
bacter cloacae, MPM meropenem
(2S,4S)-4-Acetylthio-1-p-nitrobenzyloxycarbonylpyrrolidin-2-isocyanate
(4)
N-Methylmorpholine (51.8 g, 513 mmol) and diphenylphosphorazidate
(140 g, 513 mmol) were added to a solution of compound 3 (63.0 g, 171
mmol) in dried benzene (450 ml) and stirred at 50–60 °C for 10 h. After
cooling, removal of the solvent gave an oily residue, which was chromatogra-
phed on silica gel using ethyl acetate/n-hexane (1:2) to give 4, yield 31.5 g
(50.0%).– mp 71–73 °C (dec.).– IR (KBr) ν= 1682 cm–1 (C=O), 2148
(NCO).– 1H NMR (CDCl3) δ= 2.03–2.36 (m, 1H, Ha3), 2.35 (s, 3H, COCH3),
2.60–2.79 (m, 1H, Hb3), 3.49–3.54 (m, 1H, H4), 3.90–4.02 (m, 2H, H5),
5.17–5.23 (m, 2H, CH2-aromatic), 6.63–6.71 (m, 1H, H2), 7.52 (d, J = 9.0
Hz, 2H, PNZ H), 8.22 (d, J=9.0 Hz, 2H, PNZ H).
Coupling of thiols 8a–l and the carbapenem nucleus and
deprotection of p-nitrobenzyloxycarbonyl and p-nitrobenzyl
groups were carried out in the usual manner to obtain the
[4]
target carbapenem analogs 1a–l (Scheme 3).
Antibacterial Activity
In vitro antibacterial activities of new carbapenems having
a proline reverse amide are shown in Table 1. The minimal
inhibitory concentrations (MICs) of these compounds were
determined by the Mueller-Hinton agar dilution method and
compared with meropenem as a control.
(2S,4S)-4-Acetylthio-1-p-nitrobenzyloxycarbonyl-2-p-methoxybenzyloxy-
carboaminopyrrolidine (5)
N-Methylmorpholine (16.6 g, 164 mmol) and p-methoxybenzyl alcohol
(12.5 g, 82.0 mmol) were added to a solution of compound 4 (30.0 g, 82.0
mmol) in dried benzene (350 ml) and stirred at 60–70 °C for 10 h. After
Arch. Pharm. Pharm. Med. Chem. 331, 139–142 (1998)

New Carbapenems
141
cooling, removal of the solvent gave an oily residue, which was chromatogra-
phed on silica gel using ethyl acetate/n-hexane (1:2) to give 4, yield 18.5 g
(45.0%).– mp 126–128 °C (dec.).– IR (KBr)ν= 1682 cm–1 (C=O).– 1H NMR
(CDCl3) δ= 2.16–2.18 (m, 1H, Ha3), 2.34 (s, 3H, COCH3), 2.62–2.70 (m,
1H, Hb3), 3.48–3.53 (m, 1H, H4), 3.79 (s, 3H, OCH3), 3.89–4.05 (m, 2H,
H5), 5.19–5.27 (m, 2H, CH2-aromatic), 5.60–5.71 (m, 1H, H2), 6.85, 7.24
(each-d, 4H, PMB H), 7.52, 8.23 (each-d, 4H, PNZ H).
over Na2SO4. Removal of the solvent gave an oily residue, which was
chromatographed on silica gel using ethyl acetate/methanol (10:1) to give
10i as an oil, yield 75 mg (20.0%).– 1H NMR (CDCl3) δ = 1.28 (d, J = 7.2
Hz, 3H, 1-CH3), 1.33 (d, J = 7.2 Hz, 3H, CH3CHOH), 2.00–2.18 (m, 1H,
Ha4′), 2.89–2.95 (m, 1H, Hb4′), 3.28–3.36 (m, 2H, H2′), 3.69–3.78 (m, 1H,
H6), 3.85–3.94 (m, 2H, H3′ and H5), 4.24–4.38 (m, 2H, CH3CHOH, H1),
5.09–5.24 (m, 4H, CH2x2-aromatic), 6.34–6.42 (m, 1H, H5′), 7.34–7.52 (m,
5H, PNB 2H, PNZ 2H and nicotyl 1H), 7.62–7.65 (m, 2H, PNB 2H),
7.93–8.03 (m, 1H, nicotyl 1H), 8.14–8.16 (m, 2H, PNZ 2H), 8.70–8.82 (m,
1H, nicotyl H), 8.94–9.03 (m, 1H, nicotyl H).
(2S,4S)-4-Acetylthio-1-p-nitrobenzyloxycarbonyl-2-aminopyrrolidine (6)
Trifluoroacetic acid (4.5 ml, 57.9 mmol) was added to a solution of
compound 5 (634 mg, 1.28 mmol) in dichloromethane (10 ml) and stirred at
room temperature for 3 h. The reaction mixture was concentrated in vacuo
to give an oily residue. The resulting residue was alkalized with satd.
NaHCO3 and extracted with ethyl acetate. The organic layer was washed
with water and dried over Na2SO4. Removal of the solvent gave a crude
compound 6 as an oil, yield 355 mg (83.0%), which was used to the next step
without purification.
General procedure for the preparation of carbapenems 1a–m
The appropriate compound 10 (0.10 mmol) and 10% Pd/C (35.0 mg) were
dissolved in THF/phosphate buffer (pH=7) (1:1, 10 ml each). The mixture
was hydrogenated at 50–60 psi at room temperature for 3h. The solution was
filtered through celite and washed with water. The filtrate and washings were
diluted with ethyl acetate. The separated aqueous layer was lyophilized to
give a residue, which was purified on a Diaion HP-20 column by eluting with
1% THF in water. Fractions having a UV absorption at 298 nm were collected
and lyophilized again to give the title compound 1 as a white powder.
(2S,4S)-4-Acetylthio-1-p-nitrobenzyloxycarbonyl-2-nicotylaminopyrrol-
idine (7i)
1,3-Dicyclohexylcarbodiimide (DCC) (390 mg, 1.89 mmol) and N,N′-di-
methylaminopyridine (DMAP) (10 mg) were added to a solution of nicotic
acid (233 mg, 1.89 mmol) in THF (10 ml) and stirred at room temperature
for 30 min. To this solution was added compound 6 (355 mg, 1.05 mmol).
After stirring for 6 h, the reaction mixture was filtered and the filtrate was
evaporated under reduced pressure to give an oily residue. The resulting
residue was chromatographed on silica gel using ethyl acetate/n-hexane (3:1)
to give 7i as an oil, yield 200 mg (36.0%).– 1H NMR (CDCl3) δ= 1.91–1.99
(m, 1H, Ha3), 2.34 (s, 3H, COCH3), 2.54–2.75 (m, 1H, Hb3), 3.28–3.34 (m,
1H, H4), 3.91–4.12 (m, 2H, H5), 5.09–5.21 (m, 2H, CH2-aromatic), 6.08–
6.14 (m, 1H, H2), 7.26–7.39 (m, 3H, PNZ 2H and nicotyl 1H), 8.00–8.15 (m,
3H, PNZ 2H and nicotyl 1H), 8.62 (d, 1H, nicotyl H), 8.88 (s, 1H, nicotyl
H).
(1R,5S,6S)-6-[(1R)-1-Hydroxyethyl]-2-[(3S,5S)-5-acetylaminopyrrolidin-
3-ylthio]-1-methylcarbapen-2-em-3-carboxylic acid (1a)
Yield 37.2%.– 1H NMR (D2O) δ = 1.26 (d, J = 7.3 Hz, 3H, 1-CH3), 1.33
(d, J = 6.2 Hz, 3H, CH3CHOH), 2.03-2.10 (s and m, 4H, NHCOCH3 and
Ha4′), 2.93–2.98 (m, 1H, Hb4′), 3.41–3.54 (m, 3H, H2′ and H6), 3.72–3.78
(m, 1H, H3′), 4.08–4.10 (m, 1H, H5), 4.27–4.31 (m, 2H, CH3CHOH, H1),
5.53–5.59 (m, 1H, H5′).
(1R,5S,6S)-6-[(1R)-1-Hydroxyethyl]-2-[(3S,5S)-5-isopropionylamino-
pyrrolidin-3-ylthio]-1-methylcarbapen-2-em-3-carboxylic acid (1b)
Yield 35.1%.– 1H NMR (D2O) δ = 1.13 [d, J = 6.6 Hz, 6H, COCH (CH3)2],
1.24 (d, J = 7.1 Hz, 3H, 1-CH3), 1.30 (d, J = 6.3 Hz, 3H, CH3CHOH),
2.02–2.10 (m, 1H, Ha4′), 2.57–2.63 [m, 1H, COCH(CH3)2], 2.89–2.94 (m,
1H, Hb4′), 3.40–3.50 (m, 3H, H2′ and H6), 3.67–3.73 (m, 1H, H3′), 4.01–4.05
(m, 1H, H5), 4.24–4.28 (m, 2H, CH3CHOH, H1), 5.49–5.55 (m, 1H, H5′).
(2S,4S)-4-Acetylthio-1-p-nitrobenzyloxycarbonyl-2-p-nitrobenzylamino-
pyrrolidine (7m)
N-Methylmorpholine (552 mg, 5.46 mmol) and p-nitrobenzyl alcohol
(417 mg, 2.73 mmol) were added to a solution of compound 4 (1.0 g, 2.73
mmol) in dried benzene (20 ml) and stirred at 60–70 °C for 10 h. After
cooling, removal of the solvent gave an oily residue, which was chromatogra-
phed on silica gel using ethyl acetate/n-hexane (1:2) to give 7m, yield 640
mg (45.0 %).– 1H NMR (CDCl3) δ = 2.10–2.15 (m, 1H, Ha3), 2.36 (s, 3H,
COCH3), 2.69–2.73 (m, 1H, Hb3), 3.51–3.55 (m, 1H, H4), 3.92–3.93 (m, 1H,
H5), 3.98–4.02 (m, 1H, H5), 5.17–5.21 (m, 4H, CH2x2-aromatic), 5.72–5.74
(m, 1H, H2), 7.49–7.51 (m, 4H, PNZ H), 8.17–8.19 (m, 4H, PNZ H).
(1R,5S,6S)-6-[(1R)-1-Hydroxyethyl]-2-[(3S,5S)-5-cyclopropionylamino-
pyrrolidin-3-ylthio]-1-methylcarbapen-2-em-3-carboxylic acid (1c)
Yield 35.3%.– 1H NMR (D2O) δ = 0.77–0.80 (m, 2H, CH2-cyclopropyl),
0.98–1.08 (m, 2H, CH2-cyclopropyl), 1.42–1.46 (m, 1H, COCH-cyclo-
propyl), 1.26 (d, J = 7.3 Hz, 3H, 1-CH3), 1.32 (d, J = 7.2 Hz, 3H, CH3CHOH),
2.02–2.16 (m, 1H, Ha4′), 2.89–2.96 (m, 1H, Hb4′), 3.40–3.49 (m, 3H, H2′
and H6), 3.92–4.08 (m, 2H, H3′ and H5), 4.26–4.40 (m, 2H, CH3CHOH,
H1), 5.51–5.57 (m, 1H, H5′).
General procedure for preparation of compounds 8a–m
The solution of 2N NaOH (0.3 ml) was added dropwise to a solution of
appropriate alkylthio compound 7 (0.45 mmol) in methanol (10 ml) at 0 °C
and stirred for 30 min at the same temperature. After addition of 1N HCl
(0.6 ml), the reaction mixture was concentrated in vacuo to give an oil residue
and extracted with ethyl acetate. The organic layer was washed with water
and dried over Na2SO4. Removal of the solvent gave a crude compound 8 ,
which was used to the next step without purification.
(1R,5S,6S)-6-[(1R)-1-Hydroxyethyl]-2-[(3S,5S)-5-aminoacetylamino-
pyrrolidin-3-ylthio]-1-methylcarbapen-2-em-3-carboxylic acid (1d)
Yield 74.2%.– 1H NMR (D2O) δ = 1.26 (d, J = 7.2 Hz, 3H, 1-CH3), 1.32
(d, J = 6.3 Hz, 3H, CH3CHOH), 1.96–2.12 (m, 1H, Ha4′), 2.90–3.02 (m, 1H,
Hb4′), 3.34–3.53 (m, 5H, H6, H2′ and COCH2NH2), 3.65–3.81 (m, 1H, H3′),
4.01–4.11 (m, 1H, H5), 4.23–4.30 (m, 2H, CH3CHOH and H1), 5.61–5.69
(m, 1H, H5′).
p-Nitrobenzyl-(1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-2-[(3S,5S)-(5-nicotyl-
amino-1-p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio]-1-methylcarbapen-
2-em-3-carboxylate (10i)
To a solution of p-nitrobenzyl-(1R,5S,6S)-3-diphenylphosphoryloxy-6-
[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate 9 (prepared
from 0.68 mmol of diazo keto ester) and N,N-diisopropylethylamine (106
mg, 0.82 mmol) in acetonitrile (10 ml) was added diphenylchlorophosphate
(213 mg, 0.82 mmol) at 0 °C under N2. After stirring for 3 h, the reaction
mixture was cooled to –30 °C.
N,N-Diisopropylethylamine (106 mg, 0.82 mmol) and compound 8i was
added to this mixture, and then stirred at room temperature for 8 h. The
reaction mixture was diluted with ethyl acetate, washed with water and dried
(1R,5S,6S)-6-[(1R)-1-Hydroxyethyl]-2-[(3S,5S)-5-aminopropionylamino-
pyrrolidin-3-ylthio]-1-methylcarbapen-2-em-3-carboxylic acid (1e)
Yield 79.0%.– 1H NMR (D2O) δ = 1.28 (d, J = 7.2 Hz, 3H, 1-CH3), 1.32
(d, J = 6.3 Hz, 3H, CH3CHOH), 1.99–2.22 (m, 1H, Ha4′), 2.81 (t, 2H,
COCH2CH2NH2), 2.90–3.01 (m, 1H, Hb4′), 3.32 (t, 2H, COCH2CH2NH2),
3.39–3.50 (m, 3H, H6 and H2′), 3.70–3.78 (m, 1H, H3′), 4.02–4.11 (m, 1H,
H5), 4.21–4.29 (m, 2H, CH3CHOH and H1), 5.50–5.57 (m, 1H, H5′).
Arch. Pharm. Pharm. Med. Chem. 331, 139–142 (1998)

142
Park and co-workers
(1R,5S,6S)-6-[(1R)-1-Hydroxyethyl]-2-[(3S,5S)-5-isonipecotylaminopyr-
rolidin-3-ylthio]-1-methylcarbapen-2-em-3-carboxylic acid (1f)
(m, 1H, H5), 4.29–4.31 (m, 2H, CH3CHOH and H1), 5.78–5.79 (m, 1H, H5′),
7.85 (d, J = 5.7 Hz, 2H, pyridyl H), 8.30 (d, J = 5.7 Hz, 2H, pyridyl H).
Yield 49.4%.– 1H NMR (D2O) δ = 1.24 (d, J = 7.2 Hz, 3H, 1-CH3), 1.32
(d, J = 6.3 Hz, 3H, CH3CHOH), 1.72–1.81 (m, 1H, Ha4′), 1.84–1.92,
2.03–2.15 (each m, 4H, CH2x2-nipecotyl), 2.67–2.72 (m, 1H, COCH-nipe-
cotyl), 2.98–3.09 (m, 1H, Hb4′), 3.11–3.16 (m, 2H, CH2-nipecotyl), 3.38–
3.54 (m, 5H, CH2-nipecotyl, H6 and H2′), 3.78–3.81 (m, 1H, H3′), 4.04–4.12
(m, 1H, H5), 4.24–4.29 (m, 2H, CH3CHOH and H1), 5.22–5.27 (m, 1H,
H5′).– MS m/z 438 (M–).
(1R,5S,6S)-6-[(1R)-1-Hydroxyethyl]-2-[(3S,5S)-5-nipecotylaminopyrrol-
idin-3-ylthio]-1-methylcarbapen-2-em-3-carboxylic acid (1k)
Yield 68.4%.– 1H NMR (D2O) δ = 1.27 (d, J = 7.2 Hz, 3H, 1-CH3), 1.32
(d, J = 6.3 Hz, 3H, CH3CHOH), 2.26–2.36 (m, 1H, Ha4′), 3.00–3.08 (m, 1H,
Hb4′), 3.42–3.47 (m, 3H, H2′ and H6), 3.73–3.82 (m, 1H, H3′), 4.08–4.12
(m, 1H, H5), 4.29–4.31 (m, 2H, CH3CHOH and H1), 5.80–5.91 (m, 1H, H5′),
8.81, 8.90, 9.23 (each-s, 3H, nipecotyl H), _ MS m/z 433 (M–).
(1R,5S,6S)-6-[(1R)-1-Hydroxyethyl]-2-[(3S,5S)-5-(2-pyrrolidinyl)-
carbonylaminopyrrolidin-3-ylthio]-1-methylcarbapen-2-em-3-carboxylic
acid (1g)
(1R,5S,6S)-6-[(1R)-1-Hydroxyethyl]-2-[(3S,5S)-5-(4-amino)-benzoyl-
aminopyrrolidin-3-ylthio]-1-methylcarbapen-2-em-3-carboxylic acid (1l)
Yield 41.1%.– 1H NMR (D2O) δ = 1.28 (d, J = 7.2 Hz, 3H, 1-CH3), 1.33
(d, J = 6.3 Hz, 3H, CH3CHOH), 2.20–2.29 (m, 1H, Ha4′), 2.95–3.04 (m, 1H,
Hb4′), 3.40–3.44 (m, 3H, H2′ and H6), 3.74–3.83 (m, 1H, H3′), 4.03–4.12
(m, 1H, H5), 4.23–4.30 (m, 2H, CH3CHOH and H1), 5.71–5.80 (m, 1H, H5′),
7.15 (d, J = 8.2 Hz, 2H, aromatic H), 7.84 (d, J = 8.2 Hz, 2H, aromatic H).
Yield 33.7%.– 1H NMR (D2O) δ = 1.25 (d, J = 7.2 Hz, 3H, 1-CH3), 1.35
(d, J = 6.2 Hz, 3H, CH3CHOH), 1.87–2.05 (m, 4H, NHCH2CH2-pyrrolid-
inyl), 2.04–2.08 (m, 1H, Ha4′), 2.82–2.92 (m, 1H, Hb4′), 3.38–3.41 (m, 2H,
H2′), 3.42–3.62 (m, 3H, NHCHCH2-pyrrolidinyl and H6), 3.72–3.78 (m, 2H,
H3′ and H5), 4.23–4.28 (m, 3H, NHCHCH2-pyrrolidinyl, CH3CHOH and
H1), 5.65–5.71 (m, 1H, H5′).
(1R,5S,6S)-6-[(1R)-1-Hydroxyethyl]-2-[(3S,5S)-5-aminopyrrolidin-3-yl-
thio]-1-methylcarbapen-2-em-3-carboxylic acid (1m)
(1R,5S,6S)-6-[(1R)-1-Hydroxyethyl]-2-[(3S,5S)-5-(2-furanyl)-carbonyl-
Yield 8.8%.– 1H NMR (D2O) δ = 1.28 (d, J = 7.2 Hz, 3H, 1-CH3), 1.34
(d, J = 6.2 Hz, 3H, CH3CHOH), 2.08–2.11 (m, 1H, Ha4′), 2.51–2.56 (m, 1H,
Hb4′), 3.32–3.49 (m, 2H, H2′), 3.52–3.59 (m, 1H, H6), 3.61–3.70 (m, 1H,
H3′), 4.04–4.18 (m, 1H, H5), 4.24–4.32 (m, 2H, CH3CHOH and H1),
5.72–5.81 (m, 1H, H5′).
aminopyrrolidin-3-ylthio]-1-methylcarbapen-2-em-3-carboxylic acid (1h)
Yield 27.2%.– 1H NMR (D2O) δ = 1.25 (d, J = 7.2 Hz, 3H, 1-CH3), 1.34
(d, J = 6.2 Hz, 3H, CH3CHOH), 2.02–2.14 (m, 1H, Ha4′), 2.86–2.96 (m, 1H,
Hb4′), 3.30–3.42 (m, 2H, H2′), 3.58–3.68 (m, 1H, H6), 3.74–3.78 (m, 2H,
H3′ and H5), 4.06–4.12 (m, 2H, CH3CHOH and H1), 5.59–5.65 (m, 1H, H5′),
6.52 (s, 1H, furanyl H), 7.02–7.10 (d, J = 7.4 Hz, 1H, furanyl H), 8.02–8.10
(d, J = 7.8 Hz, 1H, furanyl H).
References
[1] J. S. Kahan, F. M. Kahan, R. Goegelman, S. A. Currie, M. Jackson, E.
O. Stapley, T. W. Miller, D. Hendlin, S. Mochales, S. Hernandez, H.
B. Woodruff, J. Birnbaum. J. Antibiotics 1979, 32, 1–12.
(1R,5S,6S)-6-[(1R)-1-Hydroxyethyl]-2-[(3S,5S)-5-nicotylaminopyrrolidin-
3-ylthio]-1-methylcarbapen-2-em-3-carboxylic acid (1i)
Yield 85.0%.– 1H NMR (D2O) δ = 1.28 (d, J = 7.2 Hz, 3H, 1-CH3), 1.33
(d, J = 6.3 Hz, 3H, CH3CHOH), 2.26–2.28 (m, 1H, Ha4′), 3.01–3.06 (m, 1H,
Hb4′), 3.42–3.53 (m, 3H, H2′ and H6), 3.77–3.83 (m, 1H, H3′), 4.09–4.13
(m, 1H, H5), 4.29–4.31 (m, 2H, CH3CHOH and H1), 5.78–5.80 (m, 1H, H5′),
7.64–7.69 (m, 1H, pyridyl H), 8.30 (d, J = 8.7 Hz, 1H, pyridyl H), 8.79 (s,
1H, pyridyl H), 8.99 (s, 1H, pyridyl H).
[2] D. H. Shih, F. Baker, L. Cama, B. G. Christensen. Heterocycles 1984,
21, 29–40.
[3] D. H. Shih, L. Cama, B. G. Christensen. Tetrahedron Lett. 1985, 26,
587–590.
[4] M. Sunagawa, H. Matsumura, T. Inoue, M. Fukasawa, M. Kato. J.
Antibiotics 1990, 43, 519–532.
[5] S. W. Park, M. H. Kim, K. J. Shin, Korean J. Med. Chem. 1994, 4,
(1R,5S,6S)-6-[(1R)-1-Hydroxyethyl]-2-[(3S,5S)-5-isonicotylaminopyrrol-
16–25.
idin-3-ylthio]-1-methylcarbapen-2-em-3-carboxylic acid (1j)
Yield 75.7%.– 1H NMR (D2O) δ = 1.27 (d, J = 7.2 Hz, 3H, 1-CH3), 1.31
(d, J = 6.3 Hz, 3H, CH3CHOH), 2.22–2.31 (m, 1H, Ha4′), 2.98–3.07 (m, 1H,
Hb4′), 3.40–3.45 (m, 3H, H2′ and H6), 3.76–3.83 (m, 1H, H3′), 4.08–4.14
[6] S. Hibino, T. Choshi, S. Yamada, E. Sugino, T. Kuwada, J. Org. Chem.
1995, 60, 5899–5904.
Received: January 12, 1998 [FP273]
Arch. Pharm. Pharm. Med. Chem. 331, 139–142 (1998)