Synthesis and Antibacterial Activities of 4-Pyrrolidinylthio Carbapenems: Containing Heteroaromatics as a Side Chain

Article abstract of DOI:10.1002/ardp.200300728

The synthesis of a new series of 2-alkyl-4-pyrrolidinylthio-b-methylcarbapenems containing the substituted heteroaromatic moieties is described. Their in vitro antibacterial activities against both gram-positive and gram-negative bacteria were tested. The effect of substituents on the nitrogen atoms at heteroaromatic rings was investigated. Particular compounds (14b, 14c) containing 3-methyl- and 3,5-dimethylpyrazolethio substituted moiety showed the most potent antibacterial activity.

Full text of DOI:10.1002/ardp.200300728

Arch. Pharm. Pharm. Med. Chem. 2003, 336, 495–503
Synthesis and Antibacterial Activities of 4-Pyrrolidinylthio Carbapenems 495
Han-Won Choa,
Synthesis and Antibacterial Activities of
4-Pyrrolidinylthio Carbapenems: Containing
Heteroaromatics as a Side Chain
Chang-Hyun Oha,
Ju-Shin Leea,
Soo-Chul Leec,
Jung-Hoon Choib,
Jung-Hyuck Choa
The synthesis of a new series of 2-alkyl-4-pyrrolidinylthio-b-methylcarbapenems
containing the substituted heteroaromatic moieties is described.Their in vitro anti-
bacterial activities against both gram-positive and gram-negative bacteria were
tested.The effect of substituents on the nitrogen atoms at heteroaromatic rings was
investigated. Particular compounds (14 b, 14 c) containing 3-methyl- and 3,5-
dimethylpyrazolethio substituted moiety showed the most potent antibacterial activi-
ty.
a
Medicinal Chemistry
Research Center,
Korea Institute of Science
and Technology,
Seoul, Korea
Department of Chemistry,
Keywords: Carbapenems; Antibacterials; DHP-I stability
b
Hanyang University,
Seoul, Korea
Hawon Pharm. Co.,
Received: September 23, 2002; Accepted: November 28, 2003 [FP728]
DOI 10.1002/ardp.200300728
c
Seoul, Korea
and stability to DHP-I, 1-β-methyl-2-(5-substituted
pyrrolidin-3-yl-thio)carbapenems, bearing 2-substituted
Introduction
The discovery and development of new antibiotics has
drawn significant attention in recent years due to the ris-
ing prevalence of multidrug-resistant bacteria.Imipenem
[1], the first marketed carbapenem antibiotic, is highly
valued in the clinic for its efficacy against serious bacteri-
al infections. However, due to its instabilily to renal dehy-
dropeptidase-I (DHP-I), Imipenem is used in combina-
tion with cilastatin, a DHP-I inhibitor. In 1984, Merck re-
searchers [2] reported that the installment of a methyl
group at the β-position of the carbapenem nucleus
greatly improved both, the chemical and metabolic sta-
bilities.
heteroaromatic compounds, were prepared.
Chemistry
Our general synthetic route leading to new carbapen-
ems involved the preparation of appropriately protected
thiols containing heteroatoms as a side chain and their
coupling reaction with the carbapenem diphenylphos-
phates, followed by deprotection of the resulting protect-
ed carbapenems in a usual manner.
In summary, the acetylthio derivatives (10 a–j) were pre-
pared by the sequence shown in Scheme 1. 4-Hydroxy-
proline (1) was treated with acetylchloride in MeOH un-
der reflux to give the methyl ester (2), which was protect-
ed by allyl chloroformate to give 3 in high yield. Next, the
hydroxy group of the N-protected compound (3) was pro-
tected with tert-butyldimethylchlorosilyl chloride (TBDM-
SCl) in the presence of imidazole in DMF at 0 oC leading
to 4.This compound was reduced with NaBH4 in EtOH to
give 5, which was converted to the corresponding me-
sylate (6) with mesylchloride in CH2Cl2.The compounds
(7 a–j) were prepared by displacement of mesylate
group with the heteroaromatics (a–j) as nucleophiles un-
der basic conditions (NaH, t-BuOK) in DMF. Deprotec-
tion of the silyl ethers with 1 M tetrabutylammonium fluo-
ride (TBAF) gave hydroxyl compounds (8 a–j), which
were subsequently converted to the mesylates (9 a–j)
with mesyl chloride. Treatment of 9 a–j with potassium
thioacetate in DMF and followed by hydrolysis of the re-
sulting acetylthio groups (10 a–j) led to the thiol com-
The carbapenem compounds with a pyrrolidine-3-ylthio
group at the C-2 position in the carbapenem skeleton are
noted for their broad and potent antibacterial activity
[3–5]. Consequently a large number of derivatives has
been synthesized and investigated [6–9]. Previously, we
reported the synthesis and biological properties of car-
bapenems having the thiazolidinopyrrolidine and di-
azabicylcle moieties [10, 11].
In this report, we examined the relationship between the
spacer length and activities in a related series to
FR21818 [12, 13] that contains a carbon-nitrogen bond
as the point of attachment of the heterocycles.
As a part of our program developing a new parental 1-
β-methylcarbapenem with improved properties, activity,
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, e-mail: choh@kist.re.kr and hwcho@kist.re.kr
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

496 Cho et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 495–503
pounds (11 a–j), which were reacted with 12, in situ, using in
the presence of diisopropylethylamine to provide the corre-
sponding 2-substituted carbapenems (13 a–j) (Scheme 2).
Catalytic hydrogenation of the allyl esters resulted in the
crude products, which were purified by HP-20 column chro-
matography yielding the pure carbapenems (14 a–j).
bacteria are listed in Table 1. For comparison, the MIC
(minimum inhibitory concentration) values of Imipenem
(IPM) and Meropenem (MPM) are also listed. Com-
pound (14 c) exhibited superior or similar antibacterial
activity to Meropenem and Imipenem against gram-pos-
itive and gram-negative bacteria, except P. aeruginosa.
Heteroaromatics with electron donating methyl or iso-
propyl groups were generally observed to have better
activities than heteroaromatics with nitro or aldehyde
groups which are electron withdrawing (14 g, 14 h)
against gram-positive and gram-negative bacteria.
Among the three classes of compounds (pyrazole, imid-
azole, triazole), imidazole moieties showed the best ac-
Results and discussion
The in vitro antibacterial activities of the new carbapen-
ems (14 a–j) against gram-positive and gram-negative
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2003, 336, 495–503
Synthesis and Antibacterial Activities of 4-Pyrrolidinylthio Carbapenems 497
Table 1. In vitro antibacterial activity (MIC, µg/mL) and DHP-1 stability of the carbapenem derivatives.
STRAINS
14 a 14 b 14 c 14 d 14 e
14 f 14 g 14 h
14 i
14 j IMPa MPMb
Streptococcus pyogenes 77A
Staphylococcus aureus SG511
Staphylococcus aureus 503
Escherichia coli DC2
0.01 <0.01 <0.01 0.05 0.01 <0.01 0.01 0.02 <0.01 <0.01 <0.01 <0.01
0.10 0.05 0.05 0.78 0.20 0.10 0.10 0.39 0.39 0.39 0.01 0.10
0.10 0.05 0.05 0.39 0.10 0.10 0.10 0.39 0.20 0.20 0.01 0.05
0.10 0.10 0.05 0.39 0.20 0.10 0.10 0.20 0.20 0.20 0.39 0.01
0.05 0.10 0.05 0.39 0.10 0.10 0.10 0.20 0.20 0.20 0.20 0.01
Escherichia coli TEM
Pseudomonas aeruginosa 1771M 0.78 0.78 0.78 3.13 0.78 1.56 0.78 3.13 3.13 3.13 0.20 0.10
Salmonella typhimurium
Klebsiella aerogenes 1522E
Enterobactor cloacae 1321E
DHP-1c
0.20 0.10 0.10 0.78 0.20 0.10 0.20 0.39 0.39 0.39 0.78 0.05
0.20 0.10 0.10 0.78 0.20 0.10 0.20 0.39 0.39 0.39 0.20 0.05
0.05 0.05 0.05 0.39 0.10 0.05 0.10 0.20 0.20 0.39 0.20 0.01
1.59 1.32 1.10 3.89 2.74 2.51 1.69 2.86 1.80 1.70 0.21 1.00
Streptococcus
pyogenes 308A
<0.01 <0.01 <0.01 0.05 0.01 <0.01 0.03 0.03 <0.01 <0.01 <0.01 0.01
a
Imipenem; b Meropenem; c Human DHP-1 stability is given relative to Meropenem.
tivities against DHP-I. All these compounds have shown
better activities than MPM and IPM.
Gemini 300 spectrometer (Varian Associates Inc., Palo Alto,
CA, USA), tetramethylsilane (TMS), as an internal standard.
The mass spectrometry system was based on a HP5989A MS
Engine (Hewlett Packard, Palo Alto, CA, USA). Diaion HP-col-
umn, Ion exchange resin (Mitsubishi Chemical Co., Tokyo, Ja-
pan).
Experimental
Measurement of in vitro antibacterial activity
Melting point (mp): Thomas Hoover apparatus (Thomas Co.,
Philadelphia, PA, USA), uncorrected. UV spectra: Hewlett
Packard 8451A UV-VIS spectrophotometer (Perkin Elmer,
Ueberlingen, Germany). IR spectra: Perkin Elmer 16F-PC FT-
IR Perkin Elmer, Norwalk, CO, USA). NMR spectra:Varian
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–1 with the same broth and in-
oculated onto agar containing serial twofold dilutions of the test
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498 Cho et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 495–503
ture was stirred for 4 h.The solution was quenched with water
and 1 N HCl and concentrated under reduced pressure and the
residue was diluted with EtOAc, washed thoroughly with water
and brine, dried over anhydrous MgSO4, and concentrated un-
der reduced pressure to give a crude residue.The residue was
purified by column chromatography (n-Hexane : EtOAc (2:1)
compounds. Organisms were incubated at 37 °C for 18–20 h.
The MICs of a compound was defined as the lowest concentra-
tion that visibly inhibited growth.
Determination of susceptibility to renal dehydropeptidase-1
(DHP-1)
1
The relative hydrolysis rate of carbapenems by porcine renal
DHP-1 was determined, taking the initial hydrolysis rate of imi-
penem as 1.0. Partially purified porcine DHP-1 (final concen-
tration, 0.3 U mL–1) was incubated with 50 µM carbapenem at
35 °C in 50 mM MOPS buffer, pH 7.0.The initial hydrolysis rate
was monitored spectrophotometrically. One unit of activity was
defined as the amount of enzyme hydrolyzing 1 µM of glycylde-
hydrophenylalanine per min when the substrate, 50 µM, was
incubated at 35 °C in 50 µM MOPS buffer, pH 7.0.
elution) to give 5 as a pale yellow oil. Yield: 78 %; H-NMR
(CDCl3): δ = –0.11 (s, 6 H), 0.69 (s, 9 H), 1.64–1.68 (m, 1 H),
1.74–1.82 (m, 1 H), 3.28 (d, 2 H, J = 1.5 Hz), 3.36–3.43 (m, 1 H),
3.52–3.58 (m, 1 H), 3.89–3.91 (m, 1 H), 4.20 (s, 1 H), 4.38–4.43
(m, 2 H), 4.49–4.53 (m, 1 H), 4.99–5.14 (m, 2 H), 5.70–5.79 (m,
1 H); 13C-NMR (CDCl3): δ = –4.83, 17.97, 25.77, 37.69, 55.71,
59.20, 65.17, 65.76, 70.04, 117.27, 132.96, 156.63; IR (KBr):
1746 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-meth-
anesulfonyloxymethyl-pyrrolidine (6)
Methyl (2S,4R)-4-Hydroxypyrrolidine-2-carboxylate hydrochlo-
ride (2)
To a solution of 5 (68.0 g, 0.22 mol) and triethylamine (34.0 mL,
0.26 mol) in CH2Cl2 (200 mL) at 0 °C a solution of methanesul-
fonylchloride (MsCl) (20.0 mL, 0.26 mol) in CH2Cl2 (100 mL)
was added dropwise. After stirring at 0 °C for 1 h, the mixture
was quenched with water and separated.The residue was dilut-
ed with EtOAc, washed thoroughly with water and brine, dried
over anhydrous MgSO4, and concentrated under reduced pres-
sure to give a crude residue. The residue was purified by col-
umn chromatography (n-Hexane :EtOAc (2:1) elution) to give 6
as a pale yellow oil.Yield: 82 %; 1H-NMR (CDCl3): δ = 0.07 (s,
6 H), 0.86 (s, 9 H), 1.93–2.13 (m, 2 H), 2.99 (s, 3 H), 3.45 (d, 2 H,
J = 1.5 Hz), 4.21–4.31 (m, 2 H), 4.40–4.43 (m, 1 H), 4.55–4.65
(m, 3 H), 5.20–5.33 (m, 2 H), 5.88–5.97 (m, 1 H); 13C-NMR
(CDCl3): δ = –4.59, 18.17, 25.92, 37.35, 38.35, 55.06, 55.50,
66.08, 70.12, 100.22, 118.11, 133.06, 155.69; IR (KBr): 1694
(C=O) cm–1.
To a solution of 1 (77.0 g, 0.59 mol) in MeOH (200 mL) ace-
tylchloride (63.0 mL, 0.88 mol) was added slowly at room tem-
perature and the reaction mixture was refluxed for 8 h. The re-
action mixture was concentrated under reduced pressure.The
residue was triturated with ethyl ether and the resulting precipi-
tate was collected by filtration, washed with ethyl ether and
dried under reduced pressure to give 2 as a white solid.Yield:
92 %; mp: 157 °C; 1H-NMR (DMSO-d6): δ = 2.03–2.20 (m, 2 H),
3.06 (d, 1 H, J = 6.0 Hz), 3.36 (dd, 1 H, J = 2.0 Hz, J = 2.1 Hz),
3.74 (s, 3 H), 4.41 (m, 2 H); 13C-NMR (DMSO-d6): δ = 40.98,
57.01, 57.14, 61.52, 72.42, 173.00; IR (KBr): 3378 (NH), 1742
(C=O) cm–1.
Methyl
carboxylate (3)
(2S,4R)-1-Allyloxycarbonyl-4-hydroxypyrrolidine-2-
A mixture of 2 (110 g, 0.76 mol) and triethylamine (221 mL,
1.67 mol) in CH2Cl2 (400 mL) was added dropwise to a solution
of allylchloroformate (100 g, 0.83 mol) in CH2Cl2 (200 mL) at
–5 °C.After stirring for 3 h at room temperature, the mixture was
extracted with CH2Cl2:H2O (1:1), dried over anhydrous MgSO4,
concentrated under reduced pressure, and chromatographed
on silica gel (n-Hexane :EtOAc (1:1) elution) to give 3 as a pale
yellow oil.Yield:88 %;1H-NMR (CDCl3):δ = 2.02–2.11 (m, 1 H),
2.26–2.38 (m, 1 H), 3.52–3.67 (m, 2 H), 3.72 (d, 3 H, J = 5.3 Hz),
4.46–4.52 (m, 2 H), 4.58 (d, 2 H, J = 3.0 Hz), 5.16–5.33 (m, 2 H),
5.80–5.97 (m, 1 H); 13C-NMR (CDCl3): δ = 39.33, 52.54, 55.39,
66.37, 69.38, 117.50, 132.64, 154.88, 173.45; IR (KBr): 3442
(NH), 1746 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-(pyr-
azol-1-ylmethyl)pyrrolidine (7 a)
To a solution of pyrazole (6.1 g, 15.5 µMol) in DMF (40 mL) at
0 °C NaH (60 % in oil, 0.87 g) was added and the mixture was
stirred for 30 min at the same temperature. The mixture was
added to a solution of 6 in DMF and stirred at 60–70 °C for 2 h.
The mixture was quenched with ice water, then diluted with
EtOAc, washed thoroughly with H2O, dried over anhydrous
MgSO4, evaporated under reduced pressure, and purified by
column chromatography (n-Hexane : EtOAc (5:1) elution) to
give 7 a as a pale yellow oil.Yield: 79 %; 1H-NMR (CDCl3): δ =
0.00 (s, 6 H), 0.82 (s, 9 H), 1.88–1.94 (m, 1 H), 2.04–2.17 (m,
1 H), 3.12–3.26 (m, 2 H), 3.62–3.70 (m, 1 H), 4.24–4.39 (m,
3 H), 5.22–5.35 (m, 2 H), 5.92–5.99 (m, 1 H), 6.26 (s, 1 H), 7.30
(s, 1 H), 7.49 (s, 1 H); 13C-NMR (CDCl3): δ = –4.77, 18.10,
25.93, 37.59, 53.33, 54.82, 57.33, 66.01, 69.64, 106.18,
117.61, 130.36, 139.55; IR (KBr): 1704 (C=O) cm–1.
Methyl
(2S,4R)-1-Allyloxycarbonyl-4-tert-butyldimethylsilyl-
oxypyrrolidine-2-carboxylate (4)
To a solution of 3 (62.0 g, 0.27 mol) in DMF (120 mL), imidazole
(44.0 g, 0.65 mol) and tert-butyldimethylchlorosilane (TBDMS-
Cl) (49.0 g, 0.33 mol) were added and the solution stirred at
room temperature for 3 h.The reaction mixture was diluted with
EtOAc, washed thoroughly with water and brine, dried over an-
hydrous MgSO4, and concentrated under reduced pressure to
give 4 as a colorless oil.Yield: 83 %; 1H-NMR (CDCl3): δ = 0.01
(s, 6 H), 0.79 (s, 9 H), 1.91–2.02 (m, 1 H), 2.08–2.16 (m, 1 H),
3.32–3.42 (m, 1 H), 3.57 (dd, 1 H, J = 2.4 Hz, J = 2.4 Hz), 3.65
(d, 3 H, J = 5.0 Hz), 4.38 (m, 2 H), 4.51 (m, 2 H), 5.16 (m, 2 H),
5.82 (m, 1 H);13C-NMR (CDCl3):δ = –4.74, 18.07, 25.82, 39.05,
52.31, 54.84, 57.91, 66.01, 69.86, 117.11, 132.85, 154.40,
173.26; IR (KBr): 1746 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-hydroxy-2-(pyrazol-1-ylmeth-
yl)pyrrolidine (8 a)
To a solution of 7 a (3.4 g, 9.30 mmol) in THF (40 mL) added a
solution of 1M tetrabutylammonium fluoride (TBAF) (14 ml,
13.95 mmol) in THF was slowly and then stirred for 2 h at room
temperature.The mixture was diluted with EtOAc, washed thor-
oughly with water and brine, dried over anhydrous MgSO4, and
concentrated under reduced pressure to give a crude residue.
The residue was purified by column chromatography (EtOAc
only for elution) to give 8 a as a pale yellow oil.Yield: 92 %; 1H-
NMR (CDCl3): δ = 1.68–1.79 (m, 1 H), 1.94–2.10 (m, 1 H), 3.11
(d, 1 H, J = 2.3 Hz), 3.15 (d, 1 H, J = 2.3 Hz), 3.41–3.45 (m, 1 H),
3.97–4.12 (m, 1 H), 4.30–4.40 (m, 3 H), 4.58–4.64 (m, 2 H),
5.23–5.36 (m, 2 H), 5.94–5.97 (m, 1 H), 6.25 (s, 1 H), 7.31 (s,
(2S,4R)-1-Allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-hy-
droxymethylpyrrolidine (5)
To a solution of 4 (118.0 g, 0.34 mol) in EtOH (400 mL) NaBH4
(65.0 g, 0.17 mol) was added at room temperature and the mix-
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Arch. Pharm. Pharm. Med. Chem. 2003, 336, 495–503
Synthesis and Antibacterial Activities of 4-Pyrrolidinylthio Carbapenems 499
1 H), 1.47 (s, 1 H); 13C-NMR (CDCl3): δ = 20.00, 25.82, 52.91,
54.82, 57.09, 66.13, 69.48, 106.19, 117.71, 130.44, 139.53; IR
(KBr): 3246 (OH), 1692 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-(im-
idazol-1-ylmethyl)pyrrolidine (7 d)
Yield: 80 %; 1H-NMR (CDCl3): δ = –0.13 (s, 6 H), 0.69 (s, 9 H),
1.55–1.61 (m, 1 H), 1.75–1.81 (m, 1 H), 3.03–3.08 (m, 1 H),
3.17–3.21 (m, 1 H), 3.65–3.67 (m, 1 H), 3.92–3.96 (m, 1 H),
4.07–4.11 (m, 1 H), 4.33–4.39 (m, 1 H), 4.52 (s, 2 H), 5.09–5.22
(m, 2 H), 5.78–5.85 (m, 1 H), 6.73 (s, 1 H), 6.91 (s, 1 H), 7.27 (s,
1 H); 13C-NMR (CDCl3): δ = –5.09, 17.73, 25.39, 37.37, 48.15,
54.78, 56.40, 65.71, 69.16, 117.36, 129.45, 132.63, 137.52,
155.33; IR (KBr): 1698 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-methanesulfonyloxy-2-(pyrazol-1-
ylmethyl)pyrrolidine (9 a)
A solution of 8 a (3.1 g, 12.34 mmol) and triethylamine (1.8 mL,
13.57 mmol) in dry CH2Cl2 (30 mL) was cooled to –5 °C under
nitrogen and treated with methanesulfonylchloride (1.05 mL,
13.57 mmol). The mixture was stirred at 0 °C for 1 h, diluted
with EtOAc, and washed with cold water and brine.The organic
layer was dried over anhydrous Na2SO4.Evaporation of the sol-
vent in vacuo gave a crude residue, which was purified by silica
gel column chromatography (n-Hexane :EtOAc (1:3) elution) to
give 9 a as a pale yellow oil.Yield: 87 %; 1H-NMR (CDCl3): δ =
2.47–2.52 (m, 3 H), 3.01 (s, 3 H), 3.15–3.19 (m, 1 H), 3.64–3.67
(m, 1 H), 4.36–4.41 (m, 3 H), 4.67–4.71 (m, 3 H), 5.26–5.37 (m,
2 H), 5.90–6.03 (m, 1 H), 6.29 (s, 1 H), 7.33 (s, 1 H), 7.52 (s,
1 H); 13C-NMR (CDCl3): δ = 29.93, 35.14, 38.74, 52.48, 52.80,
56.66, 66.42, 106.40, 118.10, 130.70, 139.97; IR (KBr): 1698
(C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-(2-
methylimidazol-1-ylmethyl)pyrrolidine (7 e)
Yield: 82 %; 1H-NMR (CDCl3): δ = –0.05 (s, 6 H), 0.77 (s, 9 H),
1.62–1.68 (m, 1 H), 1.81–1.89 (m, 1 H), 2.32 (s, 3 H), 3.18–3.41
(m, 2 H), 3.91–4.16 (m, 4 H), 4.53–4.57 (m, 2 H), 5.15–5.28 (m,
2 H), 5.84–5.93 (m, 1 H), 6.69 (s, 1 H), 6.83 (s, 1 H); 13C-NMR
(CDCl3): δ = –4.67, 13.22, 18.07, 25.84, 37.76, 47.69, 55.05,
57.12, 66.08, 69.69, 117.74, 120.09, 127.63, 132.98, 145.22,
155.71; IR (KBr): 1706 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-(2-iso-
propylimidazol-1-ylmethyl)pyrrolidine (7 f)
(2S,4S)-4-Acetylthio-1-allyloxycarbonyl-2-(pyrazol-1-ylmeth-
yl)pyrrolidine (10a)
Yield: 79 %; 1H-NMR (CDCl3): δ = 0.03 (s, 6 H), 0.79 (s, 9 H),
1.24–1.30 (m, 6 H), 1.65–1.69 (m, 1 H), 1.83–1.89 (m, 1 H),
2.95–3.03 (m, 1 H), 3.23–3.28 (m, 2 H), 3.99–4.26 (m, 4 H),
4.59–4.62 (m, 2 H), 5.18–5.32 (m, 2 H), 5.87–5.96 (m, 1 H),
6.69 (s, 1 H), 6.92 (s, 1 H); 13C- NMR (CDCl3): δ = –4.66, 18.09,
22.21, 22.45, 35.52, 37.85, 47.15, 55.21, 57.18, 66.13, 69.75,
117.77, 119.47, 127.69, 133.00, 155.86, 155.83; IR (KBr):
1702 (C=O) cm–1.
A mixture of 9 a (2.1 g, 6.38 mmol) and potassium thioacetate
(2.2 g, 19.13 mmol) in DMF (20 mL) and toluene (20 mL) was
stirred at 70 °C for 3 h under N2 gas. After cooling, the reaction
mixture was diluted with EtOAc, water and the aqueous layer
was extracted with EtOAc. The combined solvent was washed
with brine and dried over anhydrous Na2SO4. Removal of the
solvent gave a crude residue, which was purified by silica gel
column chromatography (n-Hexane : EtOAc (1:1) elution) to
give 10 a as a pale yellow oil.Yield: 77 %; 1H-NMR (CDCl3): δ =
1.83–2.04 (m, 1 H), 2.29 (s, 3 H), 2.34–2.36 (m, 1 H), 2.81–2.92
(m, 1 H), 3.65–3.85 (m, 1 H), 3.90–4.08 (m, 1 H), 4.16–4.23 (m,
1 H), 4.47 (s, 2 H), 4.60 (d, 2 H, J = 2.6 Hz), 5.21–5.34 (m, 2 H),
5.87–5.98 (m, 1 H), 6.24 (s, 1 H), 7.32 (s, 1 H), 7.47 (s, 1 H);13C-
NMR (CDCl3): δ = 30.72, 33.79, 38.86, 52.52, 52.99, 57.99,
66.29, 106.16, 118.02, 130.18, 132.87, 139.63, 154.73; IR
(KBr): 1696 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-(4-ni-
troimidazol-1-ylmethyl)pyrrolidine (7 g)
Yield: 76 %; 1H-NMR (CDCl3): δ = 0.02 (s, 6 H), 0.84 (s, 9 H),
1.58–1.65 (m, 1 H), 1.93–1.96 (m, 1 H), 2.57 (s, 3 H), 3.23–3.28
(m, 1 H), 3.42–3.46 (m, 1 H), 4.04–4.07 (m, 1 H), 4.12–4.20 (m,
1 H), 4.25–4.30 (m, 2 H), 4.65 (d, 2 H, J = 2.6 Hz), 5.24–5.36 (m,
2 H), 5.91–5.97 (m, 1 H), 7.40 (s, 1 H), 9.95 (s, 1 H); 13C-NMR
(CDCl3): δ = –4.93, 13.32, 17.93, 25.69, 37.80, 46.91, 54.82,
56.58, 66.05, 69.57, 117.74, 126.72, 132.88, 138.27, 143.15,
153.39, 178.92; IR (KBr): 1696 (C=O) cm–1.
Preparations of 7 b–j were carried out by a method similar to
that described for 7 a from the appropriate starting materials.
(2S,4R)-1-Allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-(3-
methylpyrazol-1-ylmethyl)pyrrolidine (7 b)
(2S,4R)-1-Allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-(4-
methyl-5-formylimidazol-1-yl-methyl)pyrrolidine (7 h)
Yield: 81 %; 1H-NMR (CDCl3): δ = –0.08 (s, 6 H), 0.82 (s, 9 H),
1.80–1.87 (m, 1 H), 2.02–2.14 (m, 1 H), 2.20 (s, 3 H), 3.13–3.27
(m, 2 H), 3.53–3.60 (m, 1 H), 4.11–4.26 (m, 3 H), 4.58 (d, 2 H, J
= 2.1 Hz), 5.15–5.29 (m, 2 H), 5.83–5.90 (m, 1 H), 5.95 (s, 1 H),
7.10 (s, 1 H); 13C-NMR (CDCl3): δ = –4.80, 13.62, 17.96, 25.79,
38.19, 54.29, 54.43, 57.21, 65.71, 69.41, 105.59, 117.27,
130.86, 132.62, 148.26, 155.11; IR (KBr): 1710 (C=O) cm–1.
Yield: 62 %; 1H-NMR (CDCl3): δ = –0.03 (s, 6 H), 0.78 (s, 9 H),
1.58–1.66 (m, 1 H), 1.98–2.00 (m, 1 H), 3.10–3.15 (m, 1 H),
3.40–3.58 (m, 1 H), 4.04–4.27 (m, 4 H), 4.58–4.63 (m, 3 H),
5.18–5.29 (m, 2 H), 5.83–5.94 (m, 1 H), 7.35 (s, 1 H), 7.73 (s,
1 H); 13C-NMR (CDCl3): δ = –4.70, 18.05, 25.79, 37.89, 49.68,
55.74, 56.65, 66.32, 69.57, 118.05, 120.49, 132.75, 137.09,
148.31, 156.05; IR (KBr): 1696 (C=O), 1546(C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-(3,5-
dimethylpyrazol-1-ylmethyl)pyrrolidine (7 c)
(2S,4R)-1-Allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-(1,2,4-
triazol-1-ylmethyl)pyrrolidine (7 i)
Yield: 80 %; 1H-NMR (CDCl3): δ = 0.00 (s, 6 H), 0.84 (s, 9 H),
1.84–1.92(m, 2 H), 2.21 (s, 6 H), 2.31–2.35 (m, 1 H), 3.23–3.33
(m, 2 H), 3.80–3.86 (m, 1 H), 4.15–4.23 (m, 3 H), 4.63 (d, 2 H,
J = 2.4 Hz), 5.21–5.35 (m, 2 H), 5.80 (s, 1 H), 5.92–5.96 (m,
1 H); 13C-NMR (CDCl3): δ = –4.5, 11.1, 13.9, 18.3, 26.1, 37.8,
50.8, 54.6, 57.5, 66.2, 70.0, 105.8, 117.8, 133.4, 140.0, 147.9,
155.7; IR (KBr): 1716 (C=O) cm–1.
Yield: 77 %; 1H-NMR (CDCl3): δ = 0.01 (s, 6 H), 0.81 (s, 9 H),
1.94–2.00 (m, 2 H), 3.08–3.12 (m, 1 H), 3.31–3.36 (m, 1 H),
3.83–3.85 (m, 1 H), 4.35–4.36 (m, 1 H), 4.63–4.66 (m, 3 H),
4.83–4.88 (m, 1 H), 5.19–5.33 (m, 2 H), 5.89–5.98 (m, 1 H),
7.58 (s, 1 H), 7.68 (s, 1 H); 13C-NMR (CDCl3) : δ = –5.01, 17.86,
25.67, 37.50, 50.97, 55.02, 56.49, 65.84, 69.43, 117.40,
124.79, 132.87, 133.72, 155.43; IR (KBr): 1704 (C=O) cm–1.
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

500 Cho et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 495–503
(2S,4R)-1-Allyloxycarbonyl-4-hydroxy-2-(4-nitroimidazol-1-yl-
methyl)pyrrolidine (8 g)
(2S,4R)-1-Allyloxycarbonyl-4-tert-butyldimethylsilyloxy-2-(1,2,3-
tirazol-1-ylmethyl)pyrrolidine (7 j)
1
RLD.5Yield: 69 %; 1H-NMR (CDCl3): δ = 0.00 (s, 6 H), 0.83 (s,
9 H), 1.94–1.99 (m, 2 H), 3.04–3.09 (m, 1 H), 3.33–3.36 (m,
1 H), 3.86–3.88 (m, 1 H), 4.32–4.34 (m, 1 H), 4.63–4.68 (m,
3 H), 4.86–4.91 (m, 1 H), 5.22–5.34 (m, 2 H), 5.91–5.98 (m,
1 H), 7.51 (s, 1 H), 7.70 (s, 1 H); 13C-NMR (CDCl3): δ = –4.80,
18.12, 25.88, 37.76, 51.17, 55.35, 56.73, 66.16, 69.62, 117.79,
124.83, 133.00, 134.08, 155.75; IR (KBr): 1704 (C=O) cm–1.
Yield: 90 %; H-NMR (CDCl3): δ = 1.58–1.61 (m, 1 H), 1.87–
1.89 (m, 1 H), 2.31 (s, 3 H), 3.10–3.21(m, 1 H), 3.33–3.46 (m,
1 H), 4.06–4.15 (m, 3 H), 4.39–4.44 (m, 3 H), 5.05–5.18 (m,
2 H), 5.71–5.78 (m, 1 H), 7.37 (s, 1 H), 9.68 (s, 1 H); 13C-NMR
(CDCl3): δ = 13.23, 37.48, 46.52, 54.98, 55.92, 66.18, 68.44,
117.82, 126.78, 132.70, 138.62, 142.99, 153.10, 179.18; IR
(KBr): 3390 (OH), 1680 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-hydroxy-2-(4-methyl-5-formylim-
idazol-1-ylmethyl)pyrrolidine (8 h)
Preparations of 8 b–j were carried out by a method similar to
that described for 8 a from the appropriate starting materials.
Yield: 88 %; 1H-NMR (DMSO-d6): δ = 1.70–1.89 (m, 2 H),
3.17–3.22 (m, 1 H), 3.31–3.39 (m, 1 H), 4.02–4.09 (m, 1 H),
4.14–4.28 (m, 3 H), 4.33–4.53 (m, 2 H), 5.00 (s, 1 H), 5.10–5.30
(m, 2 H), 5.30–5.94 (m, 1 H), 7.74 (s, 1 H), 8.29 (s, 1 H); 13C-
NMR (DMSO-d6): δ = 37.17, 49.95, 55.26, 56.79, 65.72, 68.38,
117.52, 122.84, 134.08, 138.46, 147.68, 155.41; IR (KBr):
3360 (OH), 1670 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-hydroxy-2-(3-methylpyrazol-1-yl-
methyl)pyrrolidine (8 b)
Yield: 92 %; 1H-NMR (CDCl3): δ = 1.95–2.00 (m, 2 H), 2.23 (s,
3 H), 3.17 (dd, 1 H, J = 2.3 Hz, J = 2.3 Hz), 3.33–3.56 (m, 2 H),
4.04–4.27 (m, 3 H), 4.63 (s, 2 H), 5.22–5.35 (m, 2 H), 5.91–5.97
(m, 1 H), 6.00 (s, 1 H), 7.19 (s, 1 H); 13C-NMR (CDCl3): δ =
13.64, 37.27, 53.46, 54.74, 57.21, 66.08, 69.01, 105.87,
117.66, 131.20, 138.69, 148.51, 155.41; IR (KBr): 3418 (OH),
1704 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-hydroxy-2-(1,2,4-triazol-1-ylmeth-
yl)pyrrolidine (8 i)
1
Yield: 91 %; H-NMR (CDCl3): δ = 1.83–1.86 (m, 2 H), 2.91–
(2S,4R)-1-Allyloxycarbonyl-4-hydroxy-2-(3,5-dimethylpyrazol-1-
ylmethyl)pyrrolidine (8 c)
2.95 (m, 1 H), 3.27–3.41 (m, 1 H), 3.85–3.91 (m, 1 H), 4.11–
4.25 (m, 2 H), 4.39–4.50 (m, 3 H), 5.01–5.13 (m, 2 H), 5.67–
5.78 (m, 1 H), 7.71 (s, 1 H), 7.90 (s, 1 H); 13C-NMR (CDCl3): δ =
33.54, 41.34, 59.10, 60.29, 70.07, 72.55, 121.71, 136.72,
148.06, 155.56, 159.50;IR (KBr):3410 (OH), 1694 (C=O) cm–1.
Yield: 93 %; 1H-NMR (CDCl3): δ = 1.80–1.85 (m, 1 H), 2.06 (s,
3 H), 2.09 (s, 1 H), 2.15 (s, 2 H), 2.14–2.22 (m, 1 H), 3.21–3.29
(m, 2 H), 3.93–3.99 (m, 2 H), 4.00–4.28 (m, 3 H), 4.50 (d, 2 H,
J = 2.4 Hz), 5.10–5.25 (m, 2 H), 5.69 (s, 1 H), 5.80–5.85 (m,
1 H); 13C-NMR (CDCl3): δ = 14.92, 17.44, 41.37, 54.45, 58.41,
61.06, 70.03, 72.84, 109.69, 121.60, 137.03, 144.08, 151.59,
159.57; IR (KBr): 3398 (OH), 1694 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-hydroxy-2-(1,2,3-tirazol-1-ylmeth-
yl)pyrrolidine (8 j)
1
Yield: 90 %; H-NMR (CDCl3): δ = 1.84–1.92 (m, 2 H), 2.96–
3.01 (m, 1 H), 3.34–3.37 (m, 1 H), 3.92–3.96 (m, 1 H), 4.20–
4.22 (m, 1 H), 4.47–4.55 (m, 3 H), 4.66–4.68 (m, 1 H), 5.07–
5.19 (m, 2 H), 5.77–5.81 (m, 1 H), 7.44 (s, 1 H), 7.53 (s, 1 H);
13C-NMR (CDCl3):δ = 37.02, 50.90, 54.79, 56.30, 65.89, 68.37,
117.50, 124.68, 132.40, 133.59, 155.36; IR (KBr): 3394 (OH),
1692 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-hydroxy-2-(imidazol-1-ylmeth-
yl)pyrrolidine (8 d)
1
Yield: 93 %; mp: 85 °C; H-NMR (CDCl3): δ = 1.53–1.59 (m,
1 H), 1.82–1.86 (m, 1 H), 3.02–3.07 (m, 1 H), 3.30–3.38 (m,
1 H), 3.82–3.86 (m, 1 H), 3.97–4.01 (m, 1 H), 4.08–4.12 (m,
1 H), 4.23–4.29 (m, 1 H), 4.46 (s, 2 H), 5.05–5.19 (m, 2 H),
5.74–5.83 (m, 1 H), 6.72 (s, 1 H), 6.80 (s, 1 H), 7.23 (s, 1 H);13C-
NMR (CDCl3): δ = 37.19, 48.46, 55.05, 56.84, 66.00, 68.13,
117.63, 120.36, 128.76, 132.70, 137.65, 155.51; IR (KBr):
3376(OH), 1692 (C=O) cm–1.
Preparations of 9 b–j were carried out by a method similar to
that described for 9 a from the appropriate starting materials.
(2S,4R)-1-Allyloxycarbonyl-4-methanesulfonyloxy-2-(3-methyl-
pyrazol-1-ylmethyl)pyrrolidine (9 b)
Yield: 90 %; 1H-NMR (CDCl3): δ = 2.20 (s, 3 H), 2.21–2.53 (m,
2 H), 2.94 (s, 3 H), 3.14–3.17 (m, 1 H), 3.34–3.87 (m, 1 H),
4.20–4.39 (m, 3 H), 4.51–4.84 (m, 3 H), 5.18–5.34 (m, 2 H),
5.86–5.95 (m, 1 H), 5.99 (s, 1 H), 7.14 (s, 1 H); 13C-NMR
(CDCl3): δ = 13.70, 35.02, 38.60, 52.54, 52.65, 56.64, 66.37,
78.44, 105.95, 117.95, 131.14, 139.08, 149.04, 154.78; IR
(KBr): 3418 (OH), 1698 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-hydroxy-2-(2-methylimidazol-1-yl-
methyl)pyrrolidine (8 e)
1
Yield: 92 %; H-NMR (CDCl3): δ = 1.69–1.77 (m, 1 H), 2.00–
2.04 (m, 1 H), 2.33 (s, 3 H), 3.31–3.36 (m, 1 H), 3.47–3.58 (m,
1 H), 3.94–4.25 (m, 5 H), 4.60–4.63 (m, 2 H), 5.22–5.36 (m,
2 H), 5.88–6.01 (m, 1 H), 6.74 (s, 1 H), 6.82 (s, 1 H); 13C-NMR
(CDCl3): δ = 12.96, 37.66, 48.02, 55.05, 57.14, 66.23, 68.53,
117.88, 120.28, 126.90, 132.96, 145.19, 155.76; IR (KBr):
3142 (OH), 1694 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-methanesulfonyloxy-2-(3,5-
dimethylpyrazol-1-ylmethyl)pyrrolidine (9 c)
Yield: 91 %; 1H-NMR (CDCl3): δ = 2.08 (s, 6 H), 2.02–2.04 (m,
1 H), 2.39–2.48 (m, 1 H), 2.84 (s, 3 H), 3.20–3.26 (m, 1 H),
3.56–3.68 (m, 1 H), 3.87–4.11 (m, 4 H), 4.44–4.48 (m, 2 H),
4.63–4.70 (m, 1 H), 5.05–5.22 (m, 2 H), 5.64 (s, 1 H), 5.73–5.82
(m, 1 H); 13C-NMR (CDCl3): δ = 10.57, 13.21, 34.98, 38.14,
49.56, 52.07, 56.45, 65.87, 78.22, 105.55, 117.57, 132.61,
139.68, 147.57, 154.55;IR (KBr):3412 (OH), 1694 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-hydroxy-2-(2-isopropylimidazol-1-
ylmethyl)pyrrolidine (8 f)
1
Yield: 91 %; H-NMR (CDCl3): δ = 1.02–1.08 (m, 1 H), 1.54–
1.61 (m, 1 H), 1.70–1.82 (m, 1 H), 2.81–2.90 (m, 1 H), 3.14–
3.16 (m, 1 H), 3.32–3.43 (m, 1 H), 3.70–3.78 (m, 1 H), 4.01–
4.16 (m, 3 H), 4.40–4.43 (m, 2 H), 4.99–5.15 (m, 2 H), 5.67–
5.78 (m, 1 H), 6.54 (s, 1 H), 6.63 (s, 1 H); 13C-NMR (CDCl3): δ =
22.28, 25.54, 37.50, 47.28, 55.05, 57.07, 65.95, 68.07, 117.56,
119.52, 126.69, 132.83, 153.67, 155.64; IR (KBr): 3346 (OH),
1666 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-methanesulfonyloxy-2-(imidazol-
1-ylmethyl)pyrrolidine (9 d)
1
Yield: 90 %; H-NMR (CDCl3): δ = 1.80–1.88 (m, 1 H), 2.26–
2.31 (m, 1 H), 2.94 (s, 3 H), 3.17–3.24 (m, 1 H), 3.76–3.80 (m,
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Pharm. Med. Chem. 2003, 336, 495–503
Synthesis and Antibacterial Activities of 4-Pyrrolidinylthio Carbapenems 501
Preparations of 10 b–j were carried out by a method similar to
that described for 10 a from the appropriate starting materials.
1 H), 4.06–4.10 (m, 1 H), 4.23–4.27 (m, 1 H), 4.47–4.53 (m,
1 H), 4.61 (s, 2 H), 4.78–4.83 (m, 1 H), 5.19–5.31 (m, 2 H),
5.83–5.93 (m, 1 H), 6.80 (s, 1 H), 7.00 (s, 1 H), 7.37 (s, 1 H);13C-
NMR (CDCl3): δ = 35.15, 38.71, 47.77, 52.99, 56.47, 66.52,
77.89, 118.31, 120.23, 129.79, 132.59, 138.07, 155.03; IR
(KBr): 1698 (C=O) cm–1.
(2S,4S)-4-Acetylthio-1-allyloxycarbonyl-2-(3-methylpyrazol-1-
ylmethyl)pyrrolidine (10 b)
Yield: 87 %; 1H-NMR (CDCl3): δ = 1.86–2.06 (m, 1 H), 2.17–2.28
(m, 7 H), 3.74–2.83 (m, 1 H), 3.96–3.99 (m, 3 H), 4.07 (s, 2 H),
4.55 (d, 2 H, J = 1.8 Hz), 5.17–5.30 (m, 2 H), 5.80–5.92 (m, 1 H),
5.95 (s, 1 H), 7.16 (s, 1 H); 13C-NMR (CDCl3): δ = 13.69, 30.53,
33.76, 38.79, 52.72, 57.85, 66.21, 105.61, 117.90, 130.91,
138.80, 148.57, 154.61, 195.24; IR (KBr): 1743 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-methanesulfonyloxy-2-(2-methyl-
imidazol-1-ylmethyl)pyrrolidine (9 e)
1
Yield: 89 %; H-NMR (CDCl3): δ = 1.77–1.83 (m, 1 H), 2.20–
2.27 (m, 4 H), 2.88 (s, 3 H), 3.25–3.31 (m, 1 H), 3.73–4.15 (m,
3 H), 4.51–4.53 (m, 2 H), 4.82–4.88 (m, 1 H), 5.11–5.24 (m,
2 H), 5.76–5.87 (m, 1 H), 6.65 (s, 1 H), 6.76 (s, 1 H); 13C-NMR
(CDCl3): δ = 13.20, 35.38, 38.63, 47.12, 52.88, 56.65, 66.40,
78.03, 118.15, 120.01, 127.82, 132.59, 145.26, 155.04; IR
(KBr): 1698 (C=O) cm–1.
(2S,4S)-4-Acetylthio-1-allyloxycarbonyl-2-(3,5-dimethylpyrazol-
1-ylmethyl)pyrrolidine (10 c)
Yield: 83 %; 1H-NMR (CDCl3): δ = 1.90–2.75 (m, 11 H), 2.97–
3.00 (m, 1 H), 3.74–2.79 (m, 1 H), 3.97–4.00 (m, 3 H), 4.40–
4.44 (m, 1 H), 4.51 (d, 2 H, J = 2.7 Hz), 5.12–5.26 (m, 2 H), 5.69
(s, 1 H), 5.80–5.86 (m, 1 H); 13C-NMR (CDCl3): δ = 10.80,
13.35, 30.46, 33.89, 39.04, 50.34, 52.55, 65.95, 105.06,
117.69, 132.51, 139.41, 147.44, 154.62, 195.06; IR (KBr):
1694 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-methanesulfonyloxy-2-(2-isopro-
pylimidazol-1-ylmethyl)pyrrolidine (9 f)
1
Yield: 88 %; H-NMR (CDCl3): δ = 1.03–1.13 (m, 6 H), 1.71–
1.79 (m, 1 H), 2.12–2.16 (m, 1 H), 2.79 (s, 3 H), 3.20–3.24 (m,
1 H), 3.64–3.80 (m, 1 H), 3.94–4.15 (m, 3 H), 4.40–4.45 (m,
2 H), 4.76–4.83 (m, 1 H), 5.01–5.14 (m, 2 H), 5.68–5.77 (m,
1 H), 6.53 (s, 1 H), 6.70 (s, 1 H); 13C-NMR (CDCl3): δ = 22.44,
25.64, 35.46, 38.55, 46.56, 52.88, 56.70, 66.31, 78.16, 118.02,
119.34, 127.67, 132.59, 153.80, 155.00; IR (KBr): 1694 (C=O)
cm–1.
(2S,4S)-4-Acetylthio-1-allyloxycarbonyl-2-(imidazol-1-ylmethyl)-
pyrrolidine (10d)
Yield: 83 %; 1H-NMR (CDCl3): δ = 1.51–1.55 (m, 1 H), 2.22 (s,
3 H), 2.27–2.31 (m, 1 H), 2.83–2.89 (m, 1 H), 3.71–3.76 (m,
1 H), 3.89–3.94 (m, 1 H), 4.05–4.07 (m, 1 H), 4.18–4.21 (m,
2 H), 4.52 (d, 2 H, J = 2.4 Hz), 5.13–5.25 (m, 2 H), 5.80–5.89 (m,
1 H), 6.79 (s, 1 H), 6.95 (s, 1 H), 7.34 (s, 1 H);13C-NMR (CDCl3):
δ = 30.70, 33.99, 38.74, 48.22, 52.54, 57.78, 66.39, 118.21,
119.99, 129.92, 132.67, 137.86, 154.82, 194.82; IR (KBr):
1695 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-methanesulfonyloxy-2-(4-nitroim-
idazol-1-ylmethyl)pyrrolidine (9 g)
1
Yield: 89 %; H-NMR (CDCl3): δ = 1.74–1.95 (m, 1 H), 2.39–
2.47 (m, 1 H), 2.51 (s, 3 H), 3.02 (s, 3 H), 3.37–3.44 (m, 1 H),
3.86–3.94 (m, 1 H), 4.32 (bs, 2 H), 4.51–4.79 (m, 3 H), 5.25–
5.37 (m, 2 H), 5.91–5.94 (m, 1 H), 7.40 (s, 1 H), 9.83 (s, 1 H);
13C-NMR (CDCl3):δ = 13.38, 25.71, 38.61, 46.77, 52.98, 56.16,
66.29, 78.27, 118.15, 126.75, 132.48, 138.46, 143.28, 155.20,
179.21; IR (KBr): 1694 (C=O) cm–1.
(2S,4S)-4-Acetylthio-1-allyloxycarbonyl-2-(2-methylimidazol-1-
ylmethyl)pyrrolidine (10 e)
Yield: 82 %; 1H-NMR (CDCl3): δ = 1.66–1.72 (m, 1 H), 2.42 (s,
3 H), 2.43–2.62 (m, 4 H), 3.13–3.19 (m, 1 H), 3.87–4.39 (m,
5 H), 4.61 (d, 2 H, J = 2.9 Hz), 5.23–5.35 (m, 2 H), 5.89–5.98 (m,
1 H), 6.77 (s, 1 H), 6.90 (s, 1 H); 13C-NMR (CDCl3): δ = 13.38,
30.87, 34.28, 39.44, 47.91, 52.91, 57.98, 66.55, 118.32,
119.93, 127.79, 132.70, 145.35, 155.12, 194.87; IR (KBr):
1696 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-methanesulfonyloxy-2-(4-methyl-
5-formylimidazol-1-ylmethyl)pyrrolidine (9 h)
1
Yield: 86 %; H-NMR (CDCl3): δ = 1.93–2.01 (m, 1 H), 2.45–
2.49 (m, 1 H), 3.02 (s, 3 H), 3.36 (dd, 1 H, J = 3.6Hz, J = 3.3 Hz),
3.89–4.07 (m, 1 H), 4.27–4.34 (m, 2 H), 4.60–4.65 (m, 3 H),
5.08 (s, 1 H), 5.24–5.33 (m, 2 H), 5.87–5.97 (m, 1 H), 7.41 (s,
1 H), 7.80 (s, 1 H); 13C-NMR (CDCl3): δ = 35.51, 38.87, 49.10,
53.37, 56.31, 66.79, 77.92, 118.60, 120.67, 132.40, 137.17,
148.39, 155.35; IR (KBr): 1698 (C=O), 1545(C=O) cm–1.
(2S,4S)-4-Acetylthio-1-allyloxycarbonyl-2-(2-isopropylimidazol-
1-ylmethyl)pyrrolidine (10 f)
1
Yield: 80 %; H-NMR (CDCl3): δ = 1.17–1.26 (m, 6 H), 1.60–
1.66 (m, 1 H), 2.26 (s, 3 H), 2.27–2.38 (m, 4 H), 2.95–3.13 (m,
1 H), 3.79–4.07 (m, 4 H), 4.53 (d, 2 H, J = 2.6 Hz), 5.15–5.26 (m,
2 H), 5.80–5.92 (m, 1 H), 6.67 (s, 1 H), 6.86 (s, 1 H); 13C-NMR
(CDCl3): δ = 22.23, 25.77, 30.78, 34.26, 39.33, 47.30, 52.80,
58.06, 66.39, 118.13, 119.25, 127.71, 132.66, 153.73, 155.01,
194.67; IR (KBr): 1696 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-methanesulfonyloxy-2-(1,2,4-tri-
azol-1-ylmethyl)pyrrolidine (9 i)
Yield: 88 %; 1H-NMR (CDCl3): δ = 2.26–2.28 (m, 2 H), 2.89 (s,
3 H), 3.04–3.10 (m, 1 H), 3.66–3.92 (m, 1 H), 4.18–4.32 (m,
3 H), 4.47–4.49 (m, 2 H), 4.86 (s, 1 H), 5.08–5.19 (m, 2 H),
5.86–5.94 (m, 1 H), 7.77 (s, 1 H), 7.93 (s, 1 H); 13C-NMR
(CDCl3): δ = 35.43, 38.65, 49.74, 53.04, 55.94, 66.32, 78.36,
118.00, 132.61, 144.61, 152.05, 154.85; IR (KBr): 1698 (C=O)
cm–1.
(2S,4S)-4-Acetylthio-1-allyloxycarbonyl-2-(4-nitroimidazol-1-yl-
methyl)pyrrolidine (10 g)
Yield: 82 %; 1H-NMR (CDCl3): δ = 1.63–1.77 (m, 2 H), 2.37 (s,
3 H), 2.52 (s, 3 H), 3.22–3.24 (m, 1 H), 3.77–3.96 (m, 1 H),
4.06–4.10 (m, 2 H), 4.26–4.28 (m, 1 H), 4.41–4.45 (m, 2 H),
5.23–5.37 (m, 2 H), 5.86–5.97 (m, 1 H), 7.44 (s, 1 H), 9.95 (s,
1 H); 13C-NMR (CDCl3): δ = 13.49, 30.75, 34.39, 38.87, 46.54,
52.44, 57.44, 66.53, 118.20, 126.87, 132.67, 138.09, 143.04,
153.62, 179.05, 194.95; IR (KBr): 1692 (C=O) cm–1.
(2S,4R)-1-Allyloxycarbonyl-4-methanesulfonyloxy-2-(1,2,3-tir-
azol-1-ylmethyl)pyrrolidine (9 j)
1
Yield: 86 %; mp: 97 °C; H-NMR (CDCl3): δ = 2.09–2.18 (m,
1 H), 2.24–2.31 (m, 1 H), 2.91 (s, 3 H), 3.03–3.08 (m, 1 H),
3.69–3.79 (m, 1 H), 4.24–4.28 (m, 1 H), 4.52–4.59 (m, 3 H),
4.76–4.80 (m, 2 H), 5.10–5.21 (m, 2 H), 5.77–5.86 (m, 1 H),
7.45 (s, 1 H), 7.57 (s, 1 H); 13C-NMR (CDCl3): δ = 35.23, 38.58,
50.42, 53.07, 56.02, 66.35, 78.44, 118.03, 125.23, 132.64,
134.03, 154.91; IR (KBr): 1698 (C=O) cm–1.
(2S,4S)-4-Acetylthio-1-allyloxycarbonyl-2-(4-methyl-5-formylim-
idazol-1-ylmeth-yl)pyrrolidine (10 h)
Yield: 80 %; 1H-NMR (CDCl3): δ = 1.61–1.76 (m, 1 H), 2.34 (s,
3 H), 2.51–2.56 (m, 1 H), 3.05–3.07 (m, 1 H), 3.86–3.93 (m,
1 H), 4.02–4.06 (m, 1 H), 4.18–4.22 (m, 1 H), 4.31–4.42 (m,
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

502 Cho et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 495–503
14 b:Yield: 55 %; UV λmax: 298 nm; mp: 122–126 °C (dec.); 1H-
NMR (D2): δ = 1.05 (d, 3 H, J = 3.6 Hz), 1.13 (d, 3 H, J = 3.5 Hz),
1.55–1.63 (m, 1 H), 2.10 (s, 3 H), 2.58–2.63 (m, 1 H), 3.17–3.32
(m, 3 H), 3.53–3.60 (m, 1 H), 3.88–3.91 (m, 1 H), 3.98–4.11 (m,
3 H), 4.34–4.38 (m, 2 H), 6.06 (s, 1 H), 7.47 (s, 1 H); IR (KBr):
3320 (OH), 1690 (C=O) cm–1.
2 H), 4.60–4.63 (m, 2 H), 5.25–5.35 (m, 2 H), 5.88–5.93 (m,
1 H), 7.41 (s, 1 H), 7.75 (s, 1 H); 13C-NMR (CDCl3): δ = 30.62,
34.23, 38.61, 49.74, 52.38, 57.47, 66.32, 117.95, 120.77,
132.51, 137.06, 148.07, 154.85, 194.64; IR (KBr): 1694 (C=O)
cm–1.
(2S,4S)-4-Acetylthio-1-allyloxycarbonyl-2-(1,2,4-triazol-1-yl-
14 c:Yield:52 %;UV λmax:298, 310 nm;mp:131–134 °C (dec.);
1H-NMR (D2): δ = 1.17 (d, 3 H, J = 3.2 Hz), 1.26 (d, 3 H, J = 3.2
Hz), 1.51–1.55 (m, 1 H), 2.15 (s, 3 H), 2.24 (s, 3 H), 2.55–2.59
(m, 1 H), 3.17–3.21 (m, 1 H), 3.30–3.34 (m, 1 H), 3.41–3.47 (m,
2 H), 3.80–3.88 (m, 2 H), 4.16–4.27 (m, 4 H), 5.96 (s, 1 H); IR
(KBr): 3360 (OH), 1692 (C=O) cm–1.
methyl)pyrrolidine (10i)
Yield: 80 %; 1H-NMR (CDCl3): δ = 1.95–2.00 (m, 1 H), 2.26 (m,
1 H), 2.38–2.44 (m, 1 H), 2.82–2.84 (m, 1 H), 3.77–3.80 (m,
1 H), 3.95–3.99 (m, 1 H), 4.12–4.14 (m, 1 H), 4.43–4.58 (m,
2 H), 5.17–5.28 (m, 2 H), 5.82–5.91 (m, 1 H), 7.87 (s, 1 H), 7.99
(s, 1 H); 13C-NMR (CDCl3): δ = 30.74, 34.10, 38.73, 50.44,
52.52, 57.43, 66.47, 118.26, 132.62, 144.22, 152.10, 154.90,
195.04; IR (KBr): 1694 (C=O) cm–1.
14 d:Yield: 51 %; UV λmax: 298 nm; mp: 140–143 °C (dec.); 1H-
NMR (D2): δ = 0.99 (d, 3 H, J = 3.5 Hz), 1.08 (d, 3 H, J = 3.2 Hz),
1.46–1.55 (m, 3 H), 2.45–2.55 (m, 1 H), 3.06–3.25 (m, 2 H),
3.35–3.41 (m, 1 H), 3.77–3.85 (m, 2 H), 3.99–4.07 (m, 2 H),
4.24–4.31 (m, 2 H), 7.04 (s, 1 H), 7.18 (s, 1 H), 7.99 (s, 1 H); IR
(KBr): 3326 (OH), 1690 (C=O) cm–1.
(2S,4S)-4-Acetylthio-1-allyloxycarbonyl-2-(1,2,3-triazol-1-yl-
methyl)pyrrolidine (10 j)
Yield: 79 %; 1H-NMR (CDCl3): δ = 1.72–1.76 (m, 1 H), 2.17 (s,
3 H), 2.29–2.32 (m, 1 H), 2.72–2.75 (m, 1 H), 3.66–3.71 (m,
1 H), 4.10–4.14 (m, 1 H), 4.47 (d, 2 H, J = 2.6 Hz), 4.59–4.63 (m,
2 H), 5.75–5.81 (m, 1 H), 7.45 (s, 1 H), 7.56 (s, 1 H); 13C-NMR
(CDCl3): δ = 30.67, 33.79, 38.57, 50.94, 52.43, 57.36, 66.29,
118.05, 124.41, 132.66, 134.05, 154.75, 194.96; IR (KBr):
1696 (C=O) cm–1.
14 e:Yield: 47 %; UV λmax: 298 nm; mp: 150–152 °C (dec.); 1H-
NMR (D2): δ = 1.08 (d, 3 H, J = 3.3 Hz), 1.15 (d, 3 H, J = 3.3 Hz),
2.52 (s, 3 H), 2.59–2.66 (m, 1 H), 3.21–3.33 (m, 2 H), 3.46–3.61
(m, 4 H), 3.88–3.94 (m, 2 H), 4.07–4.12 (m, 2 H), 4.36–4.43 (m,
2 H), 7.22 (s, 1 H), 7.32 (s, 1 H); IR (KBr): 3426 (OH), 1694
(C=O) cm–1.
14 f:Yield: 46 %; UV λmax: 298 nm; mp: 162–165 °C (dec.); 1H-
NMR (D2): δ = 1.11–1.38 (m, 12 H), 1.83–1.89 (m, 1 H), 2.80–
2.84 (m, 1 H), 3.01–3.04 (m, 1 H), 3.30–3.49 (m, 3 H), 3.63–
3.74 (m, 1 H), 3.86–3.93 (m, 1 H), 3.99–4.22 (m, 3 H), 4.65 (d,
2 H, J = 3.0 Hz), 7.41 (s, 1 H), 7.46 (s, 1 H);IR (KBr):3360 (OH),
1691 (C=O) cm–1.
Allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(imidazol-
iomethyl)pyrrolidine-4-yl]thio-6-[(1R)-1-hydroxyethyl]-4-methyl-
7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (13 a)
A solution of Allyl (4R,5S,6S)-3-(diphenylphosphoryloxy)-6-
[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-
2-ene-2carboxylate (12, 0.38 g, 0.68 mmol) in CH3CN (10 mL)
was cooled to 0 ¡É under N2. To this solution diisopropylethyl-
amine (0.12 g, 0.68 mmol) and a solution of the mercapto com-
pound 11 a (0.21 g, 0.68 mmol) in CH3CN (5 mL) was added.
After stirring for 2 hours, the mixture was diluted with EtOAc,
washed with 10 % NaHCO3 and brine, and dried over anhy-
drous MgSO4. Evaporation in vacuo yielded a foam, which was
purified by silica gel chromatography to give 13 a as a yellow
foam solid.Yield: 76 %; 1H-NMR (CDCl3): δ = 1.16 (d, 3 H, J =
3.6 Hz), 1.28 (d, 3 H, J = 3.2 Hz), 1.60–1.63 (m, 1 H), 2.34–2.39
(m, 1 H), 3.11–3.19 (m, 2 H), 3.54–3.59 (m, 1 H), 3.89–3.92 (m,
1 H) 4.02–4.39 (m, 5 H), 4.57–4.64 (m, 4 H), 4.72–4.78 (m,
1 H), 5.17–5.40 (m, 4 H), 5.41–5.94 (m, 2 H), 6.87 (s, 1 H), 7.00
(s, 1 H), 7.45 (s, 1 H); IR (KBr): 3306 (OH), 1694 (C=O) cm–1.
14 g:Yield: 48 %; UV λmax: 299 nm; mp: 170–174 °C (dec.); 1H-
NMR (D2): δ = 1.06 (d, 3 H, J = 3.5 Hz), 1.09 (d, 3 H, J = 3.2 Hz),
1.52–1.73 (m, 1 H), 2.50 (s, 3 H), 2.59–2.70 (m, 1 H), 3.24–3.33
(m, 2 H), 3.72–3.77 (m, 1 H), 4.01–4.10 (m, 4 H), 4.45 (d, 2 H,
J = 3.0 Hz), 8.51 (s, 1 H), 9.75 (s, 1 H); IR (KBr): 3346 (OH),
1690 (C=O), 1667 (C=O) cm–1.
14 h:Yield: 37 %; UV λmax: 298 nm; mp : 142–145 °C (dec.); 1H-
NMR (D2): δ = 1.06 (d, 3 H, J = 3.5 Hz), 1.14 (d, 3 H, J = 2.9 Hz),
1.34–1.59 (m, 1 H), 2.46–2.58 (m, 1 H), 3.14–3.29 (m, 3 H),
3.51–3.54 (m, 3 H), 3.64–3.74 (m, 1 H), 4.08–4.11 (m, 3 H),
7.28 (s, 1 H), 7.99 (s, 1 H); IR (KBr): 3365 (OH), 1690 (C=O)
cm–1.
14 i:Yield: 38 %; UV λmax: 298 nm; mp: 142–145 °C (dec.); 1H-
NMR (D2): δ = 0.99 (d, 3 H, J = 3.6 Hz), 1.07 (d, 3 H, J = 4.1 Hz),
1.50–1.73 (m, 1 H), 2.45–2.66 (m, 1 H), 2.89–2.93 (m, 1 H),
3.16–3.25 (m, 2 H), 3.47–3.57 (m, 2 H), 3.86–3.95 (m, 2 H),
4.05–4.07 (m, 2 H), 4.32–4.36 (m, 1 H), 7.66 (s, 1 H), 7.91 (s,
1 H); IR (KBr): 3400 (OH), 1670 (C=O) cm–1.
(4R,5S,6S)-6-[(1R)-hydroxyethyl]-4-methyl-3-[(2S,4S)-2-imid-
azoliomethyl]pyrrolidine-4-yl]thio-7-oxo-1-azabicyclo-
[3.2.0]hept-2-ene-2-carboxylate (14 a)
Compound 13 a (0.31 g, 0.16 mmol) and 0.19 g of Pd(OH)2/C
(20 %) were dissolved in THF/phosphate buffer (pH = 7) (1 : 1,
10 mL each). The mixture was hydrogenated at 45 psi for 2 h.
The solution was filtered through celite and washed with water.
The combined filtrate was washed with ethyl ether and lyophil-
ized to give a yellow powder which was purified on a Diaion
HP-20 column, eluted with 2 % THF in water. Fractions having
UV absorption at 298 nm were collected and lyophilized again
to give the title compound 14 a as a white powder.
14 j:Yield: 32 %; UV λmax: 298 nm; mp: 136–138 °C (dec.); 1H-
NMR (D2): δ = 0.94 (d, 3 H, J = 3.6 Hz), 1.06 (d, 3 H, J = 3.2 Hz),
1.31–1.35 (m, 1 H), 2.34–2.45 (m, 1 H), 2.77–2.89 (m, 1 H),
3.08–3.20 (m, 2 H), 3.32–3.50 (m, 2 H), 3.78–3.88 (m, 2 H),
3.98–4.12 (m, 3 H), 8.55 (s, 1 H), 9.44 (s, 1 H); IR (KBr): 3440
(OH), 1640 (C=O) cm–1.
Yield: 47 %; UV λmax: 298 nm; mp: 133–134 oC (dec.); 1H-NMR
(D2):δ = 1.03 (d, 3 H, J = 4.1 Hz), 1.10 (d, 3 H, J = 8.0 Hz), 1.58–
1.68 (m, 1 H), 2.59–2.69 (m, 1 H), 2.91–2.93 (m, 1 H), 3.15–
3.33 (m, 2 H), 3.50–3.60 (m, 1 H), 3.85–4.02 (m, 1 H), 4.05–
4.09 (m, 2 H), 4.30 (bs, 1 H), 4.39–4.48 (m, 2 H), 6.27 (s, 1 H),
7.52 (s, 1 H), 7.60 (s, 1 H); IR (KBr): 3350 (OH), 1675 (C=O)
cm–1.
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Tobacco,coffee,
Manfred Hesse
and other poisons
Alkaloids
Nature´s Curse or Blessing?
Contents:
2002. 414 pages, 185 images, 110 in color. Hardcover.
e 129.–* / sFr 190.– / £ 75.–
PART A: CHEMICAL ASPECTS
Introduction / Classification of Alkaloids / Structural
Analysis / Artefacts / Chiroptical Properties / Synthesis
ISBN 3-906390-24-1
*The e-Price is valid only for Germany.
PART B: BIOLOGICAL ASPECTS
Chemotaxonomy / Aspects of Biogenesis / Importance of
Alkaloids for their Producers and Owners
Alkaloids, nitrogen-containing natural substances produced by plants, animals, and micro-
organisms, have been captivating and fascinating mankind from ancient times because of
their varied and often strong physiological effects.Typical and well-known alkaloids include,
for example, cocaine, heroin, strychnine, curarine, and caffeine.
PART C: HISTORICAL ASPECTS
With its focus on structures and syntheses this book also covers the biological, biosynthetic, and
pharmacological aspects of alkaloids. A chapter detailing the cultural and historical significance
of the most important agents completes this unique compendium.
Chemistry of Alkaloids / Cultural History and Active
Principles of Selected Alkaloids
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