Synthesis and Antibacterial Activity of 1β-Methyl-2-(5-substituted oxadiazolo pyrrolidin-3-yl-thio)carbapenem Derivatives

Article abstract of DOI:10.1002/ardp.200300768

Synthesis of a new series of 1β-methylcarbapenems with a substituted oxadiazolopyrrolidine moiety is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of the substituent on

Full text of DOI:10.1002/ardp.200300768

Arch. Pharm. Pharm. Med. Chem. 2003, 336, 567–572
Synthesis and Antibacterial Activity of Carbapenem Derivatives 567
Chang-Hyun Oha,
Synthesis and Antibacterial Activity of
1␤-Methyl-2-(5-substituted oxadiazolo
pyrrolidin-3-yl-thio)carbapenem Derivatives
Hyun-Gu Donga,
Joo-Shin Leea,
Su-Chul Leeb,
Joon Hee Hongc,
Jung-Hyuck Choa
Synthesis of a new series of 1β-methylcarbapenems with a substituted oxadiazolo-
pyrrolidine moiety is described. Their in vitro antibacterial activities against both
Gram-positive and Gram-negative bacteria were tested and the effect of the substi-
tuent on the oxadiazole ring investigated. In particular, compounds 13 a and 13 c
with ester and carbamoyl substituted oxadiazole moieties showed the most potent
antibacterial activity.
a
Medicinal Chemistry
Research Center,
Korea Institute of Science
and Technology,
Seoul 130-650, Korea
Hawon pharm. Co.,
Keywords: 1β-Methylcarbapenem; Antibacterial activity; Substituent effect
b
Seoul 135-080, Korea
College of Pharmacy,
Received: January 24, 2003; Accepted: August 6, 2003 [FP768]
DOI 10.1002/ardp.200300768
c
Chosun University,
Kwangju 501-759, Korea
thiols containing pyrrolidine ring as a side chain and
subsequent coupling reaction with the carbapenem
diphenylphosphates, followed by deprotection of the
Introduction
Discovery of lβ-methyl carbapenem [1] by the Merck
group was a milestone in that it proffered the possibili-
ty of its clinical use as a single agent without dehy-
dropeptidase-I (DHP-I) inhibitor, due to improved
chemical and metabolic stability. Carbapenem com-
pounds which have a pyrrolidin-3-ylthio group at the
C-2 position in the carbapenem skeleton are noted for
their broad and potent antibacterial activity. A large
number of derivatives have been synthesized and in-
vestigated with enthusiasm. Meropenem [2, 3] and
biapenem [4, 5] have been reported to be under devel-
opment as a single agent.
resulting protected carbapenems in
manner.
a
usual
2-(5-Substituted oxadiazole) pyrrolidine derivatives
(10 a–i) were prepared by the sequence shown in
Scheme 1. N-Protected proline methyl ester was con-
verted to O-mesylate 2 by treatment of mesyl chloride,
and subsequently treated with sodium triphenylmethyl-
thioate, which was generated in situ from triphenyl-
methylmercaptan and sodium hydride in DMF to pro-
vide 3 with inversion of the C-4 configuration. 3 was
reduced with lithium borohydride in THF-EtOH and
subsequently mesylated to give 5. The treatment of
mesylate 5 with sodium cyanide in DMSO gave the
cyano compound 6, which was successfully converted
into N-hydroxyacetamidine as an intermediater by re-
action of hydroxylamine. The formation of 5Ј-substitut-
ed oxadiazole ring 7 was accomplished by reaction of
N-hydroxyacetamidine with ethyl oxalyl chloride in THF
solution. The 4Ј-ester substituted oxadiazole 7 was
converted to the amide 8 by treatment of correspond-
ing amine in EtOH. 7 was also reduced with sodium
borohydride in EtOH to give 9. Deprotection of the trityl
group to mercaptan (10 a–i) was achieved by treat-
ment of 7, 8 c–i and 9 with trifluoroacetic acid in the
presence of triethylsilane.
We have previously reported that carbapenem com-
pounds with a pyrrolidin-3-ylthio group at the C-2 posi-
tion in the carbapenem skeleton have an outstanding
broad and potent antibacterial activity. Consequently a
large number of derivatives have been synthesized
and investigated [6–13].
In this paper, we describe the synthesis and structure-
activity relationships of 1β-methylcarbapenems with a
5Ј-substituted oxadiazolo pyrrolidine-3Ј-ylthio group as
C-2 side chain. The antibacterial activity of these car-
bapenem derivatives are also discussed.
Chemistry
Finally, the reaction of 11 [9] with thiols (10 a–i) in the
presence of diisopropylethylamine, provided 2-substi-
tuted carbapenem (12 a–i). Deprotection of these com-
pounds by catalytic hydrogenation gave the crude
products, which were purified by HP-20 column to give
the pure carbapenems (13 a–i) (Scheme 2).
Our general synthetic route leading to new carbapen-
ems, involved preparation of appropriately protected
Correspondence: Jung-Hyuck Cho, Medicinal Chemistry
Research Center, Korea Institute of Science and Technology,
Seoul 130-650, Korea; Phone: +82 2 958-5150 or -5160, Fax:
+82 2 958-5189; email: choh@kist.re.kr and hwcho@kist.re.kr
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

568 Oh et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 567–572
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2003, 336, 567–572
Synthesis and Antibacterial Activity of Carbapenem Derivatives 569
Scheme 2.
Table 1. In vitro antibacterial activity (MIC, µg/mL) and DHP-I stability of carbapenem derivatives.
STRAINS
13 a 13 b 13 c 13 d 13 e
13 f 13 g 13 h
13 i Imi-
Mero-
penem penem
1 Streptococcus pyogenes 308A <0.01 <0.01 <0.01 <0.01 0.01 <0.01 0.02 0.04 0.04 <0.01
0.01
2 Streptococcus pyogenes 77A <0.01 <0.01 0.01 0.01 0.02 <0.0 0.02 0.04 0.04 <0.01 <0.01
3 Staphylococcus aureus SG511 0.05 0.05 0.05 0.20 0.20 0.10 0.40 0.40 0.40 0.01
0.10
0.10
0.03
0.03
0.20
0.03
0.05
0.03
1.00
4 Staphylococcus aureus 285
5 Eschericihia coli DC2
6 Eschericihia coli TEM
0.10 0.10 0.10 0.40 0.40 0.20 0.80 0.80 0.40 0.01
0.10 0.10 0.20 0.80 0.40 0.10 0.40 0.40 0.40 0.40
0.05 0.10 0.10 0.40 0.20 0.05 0.40 0.40 0.40 0.20
7 Psudemonas aeruginosa 9027 0.80 6.10 3.10 25.0 12.5
6.10 50
0.20 0.10 0.10 0.40 0.40 0.20 0.40 0.40 0.40 0.80
0.10 0.20 0.20 0.40 0.40 0.10 0.4 0.40 0.40 0.10
50
50
0.80
8 Salmonella typhimurium
9 Klebsiella aerogenes 1522E
10 Enterobactor cloacae 1321E
DHP-I
0.05 0.10 0.10 0.20 0.20 0.10 0.40 0.40 0.80 0.10
1.48 2.73 1.42 2.18 2.53 1.85 1.24 3.13 2.40 0.20
Gram-positive bacteria compared to Meropenem. Fur-
thermore, they exhibited improved antibacterial activity
against Gram-negative bacteria in comparison to Imi-
penem, except against P. aeruginosa.
Antibacterial activity studies
The in vitro antibacterial activities of the new carbapen-
ems (13 a–i) described above, against Gram-positive
and negative bacteria are listed in Table 1. For compari-
son, the MIC values of Imipenem and Meropenem are
also listed.Among these compounds, 13 a, 13 b and 13 c
showed superior or similar antibacterial activity against
Compounds 13 a–I, with amide, ester and hydroxy
groups at CЈ-5 position of oxadiazole, showed slight dif-
ferences in their antibacterial activities against Gram-
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

570 Oh et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 567–572
positive and Gram-negative bacteria. As expected, the
5Ј-carbamoyl, ester, hydroxy substituted compound
(13 a–c) exhibited the most potent and well balanced ac-
tivity. The effects of substituent on the oxadiazole ring
were investigated. Results showed that the larger the
size of the substituent, the lower the activity against
Pseudomonas aeruginosa. The amides series, also
show that the larger the size of the 5Ј-amide substitu-
ents, the lower the activity against Gram-positive and
negative bacteria.
(2S,4S)-4-Tritylthio-1-(allyloxycarbonyl)pyrrolidine-2-carboxylic
acid methyl ester (3)
To a stirred solution of triphenylmethylmercaptan (80.0 g, 0.29
mol) in dry DMF (600 mL), sodium hydride (11.6 g, 0.29 mol,
60 % oil suspension) was added dropwise at 0 °C, and stirred
for 1 h at room temperature.To the resulting solution was added
solution 2 (76.7 g, 0.25 mol), in dry DMF (150 mL) at 0 °C and
stirred for 3 h at room temperature. The reaction mixture was
poured into cold dilute HCl and extracted with ethyl acetate.The
organic layer was successively washed with water and dried
over anhydrous Na2SO4. Evaporation of the solvent in vacuo
gave a crude residue, which was purified by silica gel column
chromatography to give 3 (100.6 g, 82.5 %) as a pale yellow oil.
1H-NMR (CDCl3) δ 2.01 (m, 1 H), 2.55 (m, 1 H), 3.16 (bs, 1 H),
3.54 (bs, 1 H), 3.77 and 3.82 (2 s, 3 H), 3.97 (m, 1 H), 4.42 (m,
1 H), 4.55 (d, 2 H, J = 5.5 Hz), 5.26 (m, 2 H), 5.98 (m, 1 H), 7.23
(m, 9 H), 7.48 (m, 6 H).
The stability to DHP-I of most compounds was tested
and all compounds were found to be more stable than
DHP-I compared to Meropenem. In particular, com-
pound 13 b and 13 h exhibited the highest stability.
(2S,4S)-2-Hydroxymethyl-4-tritylthio-1-(allyloxycarbonyl)pyr-
rolidine (4)
Experimental
To a solution of 3 (107.3 g, 0.22 mol) in THF (800 mL), LiBH4
(4.79 g 0.22 mol) was added slowly at 0 °C and stirred for 25 h
at room temperature. The mixture was diluted with H2O
(200 mL), 1 N HCl (200 mL) and ethyl acetate (800 mL).The or-
ganic layer was dried over anhydrous Na2SO4, concentrated,
and the resulting residue purified by silica gel column chroma-
tography to give 4 (79.4 g, 78.5 %) as a pale yellow oil. 1H-NMR
(CDCl3) δ 1.98 (m, 1 H), 2.75–2.82 (m, 2 H), 3.01 (m, 1 H), 3.55
(bs, 2 H), 3.78 (m, 1 H), 4.55 (d, 2 H, J = 5.9 Hz), 5.25 (m, 3 H),
5.90 (m, 1 H), 7.27 (m, 9 H), 7.47 (m, 6 H).
Melting point (mp): Thomas Hoover apparatus, uncorrected.
UV spectra: Hewlett Packard 8451A UV-VIS spectrophotome-
ter. IR spectra: Perkin Elmer 16F-PC FT-IR. 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.
Measurement of in vitro antibacterial activity
The minimum inhibitory concentrations (MICs) were deter-
mined by the agar dilution method using test agar.An overnight
culture of bacteria in Tryptosoy broth was diluted to a final con-
centration of approximately 106 cells/mL with the same broth,
and inoculated aseptically onto agar, containing serial two fold
dilutions of test compounds. Organisms were incubated at
37 °C for 18–20 h.The MICs of a compound was defined as the
lowest concentration that visibly inhibited growth.
(2S,4S)-2-Mesyloxymethyl-4-tritylthio-1-(allyloxycarbonyl)pyr-
rolidine (5)
A solution of 4 (68.9 g, 0.15 mol) and triethylamine (24.2 mL,
0.18 mol) in dry CH2Cl2 (400 mL) was cooled to 0 °C under ni-
trogen and treated with methanesulfonyl chloride (20.6 g, 0.18
mol).The mixture was stirred at 0 °C for 1 h, diluted with CH2Cl2
(200 mL), and washed with 10 % NaHCO3 and brine. The or-
ganic layer was dried over anhydrous Na2SO4. Evaporation of
the solvent in vacuo gave a crude residue, which was purified
by silica gel column chromatography to give 5 (76.5 g, 94.8 %)
as a pale yellow oil. 1H-NMR (CDCl3) δ 1.91 (bs, 1 H), 2.11 (bs,
1 H), 2.75–2.82 (bs, 2 H), 2.99 (s, 3 H), 3.95 (bs, 1 H), 4.01 (m,
1 H), 4.22 (bs, 1 H), 4.55 (bs, 3 H), 5.31 (m, 2 H), 5.91 (m, 1 H),
7.27 (m, 9 H), 7.48 (m, 6 H).
Determination of susceptibility to renal dehydropeptidase-I
(DHP-I)
The relative hydrolysis rate of carbapenems was determined
by porcine renal DHP-I, taking the initial hydrolysis rate of Imi-
penem to be 1.0. Partially purified porcine DHP-I (final concen-
tration 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 spectrophotometric methods.One unit of ac-
tivity was defined as the amount of enzyme required to hydro-
lyze 1 µM of glycyldehydrophenylalanine per min, when 50 µM
of substrate was incubated at 35 °C in 50 mM MOPS buffer, pH
7.0.
(2S,4S)-2-Cyanomethyl-4-tritylthio-1-(allyloxycarbonyl)pyr-
rolidine (6)
A mixture of 5 (59.0 g, 0.11 mol) and sodium cyanide (10.8 g,
0.22 mol) in DMSO (300 mL) was heated at 75 °C for 5 h. The
reaction mixture was poured into ice water and extracted with
ethyl acetate (300 mL × 2).The organic layer was successively
washed with water (200 mL, × 2) and brine, and dried over an-
hydrous Na2SO4. Evaporation of the solvent in vacuo gave a
crude residue which was purified by silica gel column chroma-
tography to give 6 (45.9 g, 89.1 %) as a pale yellow oil. 1H-NMR
(CDCl3) δ 1.88 (m, 1 H), 2.19 (m, 1 H), 2.82 (d, 2 H), 2.85–3.01
(m, 2 H), 3.88 (m, 1 H), 4.55 (d, 2 H, J = 5.9 Hz), 5.29 (m, 2 H),
5.88 (m, 1 H), 7.27 (m, 9 H), 7.47 (m, 6 H).
(2S,4R)-4-Mesyloxy-1-(allyloxycarbonyl)pyrrolidine-2-carboxyl-
ic acid methyl ester (2)
A solution of 1 (94.0 g, 0.41 mol) and triethylamine (65.0 mL,
0.49 mol) in dry CH2Cl2 (600 mL) was cooled to 0 °C under ni-
trogen and treated with methanesulfonyl chloride (56.0 g, 0.49
mol).The mixture was stirred at 0 °C for 1 h, diluted with CH2Cl2
(500 mL), and washed with 10 % NaHCO3 and brine. The or-
ganic layer was dried over anhydrous Na2SO4. Evaporation of
the solvent in vacuo gave a crude residue which was purified by
silica gel column chromatography to give 2 (117.5 g, 93.2 %),
as a pale yellow oil. 1H-NMR (CDCl3) δ 2.27 (m, 1 H), 2.75 (m,
1 H), 3.02 (s, 3 H), 3.77 and 3.80 (2 s, 3 H), 3.82–3.97 (m, 2 H),
4.42 (m, 1 H), 4.57 (d, 2 H, J = 5.8 Hz), 5.25 (m, 3 H), 5.92 (m,
1 H).
(2S,4S)-2-[(5-Ethoxycarbonyl)-1,2,4-oxadiazole-3-ylmethyl]-
4-tritylthio-1-(allyloxycarbonyl) pyrrolidine (7)
To a solution of 6 (23.4 g, 0.05 mol) and hydroxylamine hydro-
chloride (10.4 g, 0.15 mol) in EtOH (250 mL) a solution of
Na2CO3 (15.9 g, 0.15 mol) in water (70 mL) was added slowly at
room temperature and stirred for 20 h at 60 °C.The mixture was
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2003, 336, 567–572
Synthesis and Antibacterial Activity of Carbapenem Derivatives 571
diluted with H2O (200 mL), then neutralized with 6 N HCl, dilut-
ed with ethyl acetate (300 mL), and washed with brine. Evapo-
ration of the solvent in vacuo gave a crude residue, which was
used without further purification.
66.5 %) as a pale yellow oil. 1H-NMR (CDCl3) δ 1.72 (bs, 1 H),
2.12 (bs, 1 H), 2.75–2.99 (bs, 5 H), 3.25 (bs, 2 H), 4.05 (bs, 1 H),
4.53 (bs, 2 H), 5.35 (m, 2 H), 5.90 (m, 1 H), 7.26 (m, 9 H), 7.47
(m, 6 H).
To the above solution in THF (200 mL), ethyloxalyl chloride
(5.60 mL, 0.05 mol) was added dropwise and heated at reflux
for 2 h.The reaction mixture was poured into 10 % NaHCO3 and
extracted with ethyl acetate (200 mL). Evaporation of the sol-
vent in vacuo gave a crude residue, which was purified by silica
gel column chromatography to give 7 (22.3 g, 76.5 %) as a pale
yellow solid. 1H-NMR (CDCl3) δ 1.48 (t, 3 H, J = 7.4 Hz), 1.85
(bs, 1 H), 2.16 (bs, 1 H), 2.85–2.98 (bs, 3 H), 3.55 (bs, 1 H), 3.89
(bs, 1 H), 4.01 (bs, 1 H), 4.26–4.51 (bs, 4 H), 5.31 (m, 2 H), 5.91
(m, 1 H), 7.26 (m, 9 H), 7.47 (m, 6 H).
(2S,4S)-2-[(5-Ethoxycarbonyl)-1,2,4-oxadiazole-3-ylmethyl]-4-
mercapto-1-(allyloxycarbonyl) pyrrolidine (10 a)
To a solution of 9 a (0.58 g, 1.0 mmol) in CH2Cl2 (2 mL), triethyl-
silane (0.13 g, 1.1 mmol) was added dropwise at 5 °C, followed
by TFA (2 mL) addition. After stirring for 30 min at room temper-
ature, the mixture was evaporated under reduced pressure.
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, which was purified by silica gel column
chromatography to give 10 a (0.25 g, 72.0 %) as a pale yellow
oil. 1H-NMR (CDCl3) δ 1.41 (t, 3 H, J = 7.4 Hz), 1.80 (bs, 1 H),
1.94 (bs, 1 H), 2.55–2.72 (bs, 2 H), 3.01–3.35 (bs, 2 H), 3.55
(bs, 1 H), 3.89 (bs, 1 H), 4.01 (bs, 1 H), 4.14 (q, 2 H, J = 7.4 Hz),
4.53 (bs, 2 H), 5.31 (m, 2 H), 5.91 (m, 1 H).
(2S,4S)-2-[(5-Carbamoyl)-1,2,4-oxadiazole-3-ylmethyl]-4-tri-
tylthio-1-(allyloxycarbonyl) pyrrolidine (8 c)
To a stirred solution of 7 (1.17 g, 2.0 mmol) in EtOH (20 mL),
ammonium hydroxide (28 %, 10 mL) was added and stirred for
3 h at 60 °C.The mixture was neutralized with 6 N HCl, diluted
with ethyl acetate (50 mL), and washed with brine.The organic
layer was dried over anhydrous Na2SO4, which was purified by
silica gel column chromatography to give 8 c (0.87 g, 78.1 %) as
a pale yellow oil. 1H-NMR (CDCl3) δ 1.82 (bs, 1 H), 2.11 (bs,
1 H), 2.71–2.91 (bs, 3 H), 3.25 (bs, 2 H), 4.01 (bs, 1 H), 4.51 (bs,
2 H), 5.35 (m, 2 H), 5.90 (m, 1 H), 6.55 (bs, 1 H), 6.78 (bs, 1 H),
7.26 (m, 9 H), 7.47 (m, 6 H).
Compounds 10 b–i were prepared by the same procedure as
described for 10 a.
Allyl (1R,5S,6S)-6-[(1R)-hydroxyethyl]-3-[5-(4-ethoxycarbonyl-
1,2,4-oxadiazole-2-ylmethyl)-1-(allyloxycarbonyl)pyrrolidin-3-
ylthio]-1-methylcarbapen-2-em-3-carboxylate (12 a)
A solution of allyl (1R,5S,6S)-3-(diphenylphosphoryloxy)-6-
[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate
(11, 0.45 g, 0.91 mmol) in CH3CN (50 mL) was cooled to 0 °C
under N2.To this, diisopropylethylamine (0.13 g, 1.0 mmol) and
a solution of the mercapto compound 10 a (0.31 g, 0.91 mmol)
in CH3CN (10 mL), were added.After stirring for 2 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 to
give 12 a (0.41 g, 71.4 %) as a yellow foam solid. 1H-NMR
(CDCl3) δ 1.25 (d, 3 H, J = 6.6 Hz), 1.31–1.37 (dd, 6 H, J = 6.6
Hz), 1.98 (bs, 1 H), 2.14 (m, 1 H), 2.46 (m, 1 H), 2.95 (m, 2 H),
3.45 (d, 2 H, J = 9.6 Hz), 3.79–3.96 (bs 2 H), 4.01–4.18 (m, 2 H),
4.43 (bs, 1 H), 4.51–4.64 (bs, 4 H), 5.32–5.48 (m, 4 H), 5.90–
5.98 (m, 2 H). IR (KBr): 3410 (OH), 3230 (NH), 1720, 1705,
1660 (C=O) cm–1.
8 d–i were also prepared as described for preparation of 8 c us-
ing the corresponding amines.
8 d: Yield 82.5 %. 1H-NMR (CDCl3) δ 1.80 (bs, 1 H), 2.11 (bs,
1 H), 2.71–2.94 (bs, 3 H), 3.03 (s, 3 H), 3.25 (bs, 2 H), 4.01 (bs,
1 H), 4.53 (bs, 2 H), 5.35 (m, 2 H), 5.91 (m, 1 H), 6.59 (bs, 1 H),
7.26 (m, 9 H), 7.47 (m, 6 H).
8 e: Yield 77.8 %. 1H-NMR (CDCl3) δ 1.77 (bs, 1 H), 2.16 (bs,
1 H), 2.73–2.91 (bs, 3 H), 3.01 (s, 6 H), 3.29 (bs, 2 H), 4.11 (bs,
1 H), 4.55 (bs, 2 H), 5.35 (m, 2 H), 5.88 (m, 1 H), 6.39 (bs, 1 H),
7.25 (m, 9 H), 7.46 (m, 6 H).
8 f: Yield 73.5 %. 1H-NMR (CDCl3) δ 1.84 (bs, 1 H), 2.28 (bs,
1 H), 2.54 (m, 1 H), 2.60–2.72 (bs, 3 H), 3.55–3.68 (t, 2 H, J =
7.0 Hz), 3.77–3.85 (m, 3 H), 4.05 (bs, 1 H), 4.50 (bs, 2 H), 5.25
(m, 2 H), 5.86 (m, 1 H), 7.24 (m, 9 H), 7.46 (m, 6 H).
(1R,5S,6S)-6-[(1R)-Hydroxyethyl]-3-[5-(4-ethoxycarbonyl-1,2,4-
oxadiazole-2-ylmethyl)pyrro lidin-3-ylthio]-1-methylcarbapen-2-
em-3-carboxylic acid (13 a)
8 g: Yield 80.7 %. 1H-NMR (CDCl3) δ 1.80 (bs, 1 H), 1.95 (bs,
2 H), 2.06 (bs, 1 H), 2.65–2.79 (bs, 3 H), 3.01 (bs, 1 H), 3.22 (bs,
1 H), 3.55 (bs, 2 H), 3.78 (bs, 2 H), 3.94 (bs, 1 H), 4.55 (bs, 2 H),
5.25 (m, 2 H), 5.96 (m, 1 H), 7.23 (m, 9 H), 7.46 (m, 6 H).
Compound 12 a (0.24 g, 0.38 mmol) and 0.1 g of Pd(OH)2
(20 %) were dissolved 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), lyophilized to give a yellow powder which was purified
on a Diaion HP-20 column, and eluted with 2 % THF in water.
Fractions with UV absorption at 298 nm were collected and
lyophilized again to give the title compound 13 a (32.0 mg,
17.9 %) as a white powder. UV λmax: 298 nm. 1H-NMR (D2O) δ
1.06 (d, 3 H, J = 6.5 Hz), 1.15 (d, 3 H, J = 5.7 Hz), 1.29 (t, 3 H, J =
6.1 Hz), 2.04 (bs, 1 H), 2.86 (m, 1 H), 3.01–3.13 (bs, 2 H), 3.53
(bs, 2 H), 3.70 (bs, 1 H), 4.10 (m, 2 H), 4.15 (q, 2 H, J = 6.1 Hz),
4.51 (bs, 1 H). IR (KBr): 3470 (OH), 3230 (NH), 1710, 1690,
1660 (C=O) cm–1. FABMS m/z 467 (M + H)+.
8 h: Yield 69.9 %. 1H-NMR (CDCl3) δ 1.75 (bs, 1 H), 2.05 (bs,
1 H), 2.62–2.87 (bs, 2 H), 3.01–3.38 (bs, 4 H), 3.55 (bs, 2 H),
3.78 (bs, 2 H), 3.94 (bs, 1 H), 4.55 (bs, 2 H), 5.25 (m, 2 H), 5.92
(m, 1 H), 7.23 (m, 9 H), 7.44 (m, 6 H).
1
8 i: Yield 76.2 %. H-NMR (CDCl3) δ 1.70 (bs, 1 H), 2.19 (bs,
1 H), 2.27 (m, 1 H), 2.63–2.90 (bs, 3 H), 3.33–3.69 (bs, 3 H),
3.77–3.83 (bs, 3 H), 4.49 (bs, 2 H), 5.26 (m, 2 H), 5.88 (m, 1 H),
7.27 (m, 9 H), 7.47 (m, 6H).
(2S,4S)-2-[(5-Hydroxymethyl)-1,2,4-oxadiazole-3-ylmethyl]-4-
tritylthio-1-(allyloxycarbonyl) pyrrolidine (9)
To a solution of 7 (11.67 g, 20.0 mmol) in EtOH (50 mL) and
THF (50 mL), NaBH4 (1.14 g, 30.0 mmol) was added slowly at
0 °C.After 1 h the mixture was diluted with H2O (40 mL), 1 N HCl
and ethyl acetate (100 mL). The organic layer was dried over
anhydrous Na2SO4, concentrated, and the resulting residue
purified by silica gel column chromatography to give 9 (7.30 g,
The preparation of 13 b–i was carried out by a procedure simi-
lar to that described for 13 a
13 b:Yield 25.0 %. UV λmax: 298 nm. 1H-NMR (D2O) δ 1.11 (d,
3 H, J = 6.9 Hz), 1.19 (d, 3 H, J = 6.2 Hz), 1.85 (m, 1 H), 2.46–
2.67 (bs, 2 H), 2.90 (m, 1 H), 3.01–3.13 (bs, 2 H), 3.20–3.30 (m,
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572 Oh et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 567–572
3 H), 3.53 (dd, 1 H, J = 5.4 and 5.8 Hz), 3.97 (bs, 1 H), 4.10 (bs,
2 H), 4.43 (m, 1 H).IR (KBr):3510 (OH), 3300 (NH), 1710, 1690
(C=O) cm–1. FABMS m/z 425 (M + H)+.
13 i: Yield 20.8 %. UV λmax: 298 nm. 1H-NMR (D2O) δ 1.09 (d,
3 H, J = 6.7 Hz), 1.14 (d, 3 H, J = 6.1 Hz), 1.75 (m, 1 H), 2.01 (m,
1 H), 2.83 (m, 1 H), 3.20–3.37 (bs, 2 H), 3.53–3.69 (m, 2 H),
3.67–3.79 (m, 2 H), 3.81 (t, 2 H, J = 6.9 Hz), 3.98 (m, 2 H), 4.09
(m, 2 H), 4.44 (bs, 1 H). IR (KBr): 3510 (OH), 3270 (NH), 1710,
1680, 1660 (C=O) cm–1. FABMS m/z 481 (M + H)+.
13 c:Yield 21.1 %. UV λmax: 298 nm. mp 125–129 °C (dec.). 1H-
NMR (D2O) δ 1.08 (d, 3 H, J = 7.2 Hz), 1.17 (d, 3 H, J = 6.3 Hz),
1.71 (m, 1 H), 2.55–2.66 (m, 2 H), 3.05 (dd, 1 H, J = 6.9 and 6.9
Hz), 3.23 (t, 1 H, J = 7.5 Hz), 3.32 (bs, 2 H), 3.55 (q, 1 H, J = 5.9
Hz), 3.75 (t, 1 H, J = 7.1 Hz), 4.11 (bs, 2 H), 4.43 (m, 1 H). IR
(KBr): 3480(OH), 3260 (NH), 1730, 1690, 1670 (C=O) cm–1.
FABMS m/z 438 (M + H)+.
Reference
[1] D.H.Shih, F.Baker, L.Cama, B.G.Christensen, Heterocy-
cles 1984, 21, 29–40.
13 d:Yield 24.3 %. UV λmax: 298 nm. 1H-NMR (D2O) δ 1.07 (d,
3 H, J = 6.9 Hz), 1.16 (d, 3 H, J = 6.4 Hz), 1.69 (m, 1 H), 2.55–
2.72 (m, 2 H), 2.88 (s, 3 H), 3.05 (dd, 1 H, J = 6.9 and 6.9 Hz),
3.25 (t, 1 H, J = 7.5 Hz), 3.34 (bs, 1 H), 3.57 (q, 1 H, J = 5.9 Hz),
3.75 (t, 1 H, J = 7.1 Hz), 4.11 (bs, 3 H), 4.44 (m, 1 H). IR (KBr):
3540 (OH), 3270 (NH), 1705, 1680, 1665 (C=O) cm–1. FABMS
m/z 452 (M + H)+.
[2] I. Sunagawa, H. Matsumura, T. Inoue, M. Fukasawa, M.
Kato, J. Antibiot. 1990, 43, 519–532.
[3] D. E. Sentochnick, G. M. Elipoulos, M. J. Ferraro, R. C.
Moellering, Antimicrob. Agents Chemother. 1990, 33,
1232–1236.
13 e:Yield 19.1 %. UV λmax: 296 nm. mp 133–134 °C (dec.). 1H-
NMR (D2O) δ 1.07 (d, 3 H, J = 6.9 Hz), 1.16 (d, 3 H, J = 6.4 Hz),
1.79 (m, 1 H), 2.65–2.78 (m, 2 H), 2.92 and 2.96 (2 s, 6 H), 3.09
(dd, 1 H, J = 6.7 and 6.7 Hz), 3.27 (t, 1 H, J = 7.5 Hz), 3.34 (bs,
1 H), 3.57 (q, 1 H, J = 5.9 Hz), 3.75 (t, 1 H, J = 7.1 Hz), 3.99 (m,
1 H), 4.11 (bs, 2 H), 4.44 (m, 1 H). IR (KBr): 3510 (OH), 3300
(NH), 1710, 1690 (C=O) cm–1. FABMS m/z 466 (M + H)+.
[4] Y. Nagao, Y. Nagase, T. Kumagai, T. Hayashi, Y. Inoue, J.
Org. Chem. 1992, 57, 4243–4249.
[5] K. Ubukata, M. Hikida, M.Yoshida, K. Hishiki, M. Konno, S.
Mitsuhashi, Antimicrob. Agents Chemother. 1992, 36,
994–1000.
[6] C.-H. Oh, S.-Y, Hong, J.-H. Cho, Korean J. Med. Chem.
1992, 2, 7–16.
13 f: Yield 23.8 %. UV λmax: 298 nm. 1H-NMR (D2O) δ 1.09 (d,
3 H, J = 6.5 Hz), 1.16 (d, 3 H, J = 6.0 Hz), 1.68 (m, 1 H), 1.98 (m,
1 H), 2.81 (m, 1 H), 3.23–3.36 (bs, 2 H), 3.57–3.64 (m, 2 H),
3.67–3.77 (m, 2 H), 3.81 (t, 2 H, J = 7.1 Hz), 3.98 (m, 2 H), 4.09
(m, 2 H), 4.44 (bs, 1 H). IR (KBr): 3510 (OH), 3270 (NH), 1710,
1680 (C=O) cm–1. FABMS m/z 482 (M + H)+.
[7] C.-H. Oh, S.-Y, Hong, K.-H. Nam, J.-H. Cho, Korean J.
Med. Chem. 1993, 3, 82–92.
[8] C.-H. Oh, E.-R. Woo, S.-Y, Hong, K.-H. Nam, D. Y. Kim,
J.-H. Cho, Korean J. Med. Chem. 1994, 4, 26–34.
13 g:Yield 16.9 %. UV λmax: 298 nm. 1H-NMR (D2O) δ 1.08 (d,
3 H, J = 7.8 Hz), 1.22 (d, 3 H, J = 7.0 Hz), 1.76–2.04 (bs, 4 H),
2.93 (m, 1 H), 3.23–3.43 (m, 2 H), 3.54–3.65 (m, 3 H), 3.71–
3.95 (m, 4 H), 4.01 (bs, 1 H), 4.21–4.29 (bs, 2 H), 4.55 (bs, 1 H).
IR (KBr): 348 (OH), 326 (NH), 1730, 1670 (C=O) cm–1. FABMS
m/z 496 (M + H)+.
[9] C.-H. Oh, J.-H. Cho, J. Antibiot. 1994, 47, 126–128.
[10] C. B. Jin, I. S. Jung, H.-J. Ku, J. W. Yook, D.-H. Kim, J.-H.
Cho, M.S. Kim, C.-H. Oh, Toxicology 1999, 138, 59–67.
[11] C.-H.Oh, H.-W.Cho, I.-K.Lee, J.-Y.Gong, J.-H.Choi, J.-H.
Cho, Arch. Pharm. Pharm. Med. Chem. 2002, 335, 152–
158.
13 h:Yield 15.9 %. UV λmax: 298 nm. 1H-NMR (D2O) δ 1.08 (d,
3 H, J = 7.7 Hz), 1.22 (d, 3 H, J = 7.1 Hz), 1.77 (m, 1 H), 1.98 (m,
1 H), 2.93 (m, 1 H), 3.23–3.43 (m, 2 H), 3.54–3.65 (m, 3 H),
3.71–3.95 (m, 5 H), 4.01 (bs, 1 H), 4.20–4.28 (bs, 2 H), 4.55 (bs,
1 H). IR (KBr): 3480 (OH), 3260 (NH), 1730, 1670 (C=O) cm–1.
IR (KBr): 3500 (OH), 3320 (NH), 1710, 1690 (C=O) cm–1.
FABMS m/z 512 (M + H)+.
[12] C.-H.Oh, H.-G.Dong, H.-W.Cho, S.J.Park, J.H.Hong, J.-
H. Cho, Arch. Pharm. Pharm. Med. Chem. 2002, 335,
200–206.
[13] C.-H. Oh, H.-W. Cho, J.-H. Cho, European J. of Med.
Chem. 2002, 37, 743–754.
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim