Synthesis and antibacterial activity of 1β-methyl-2-(5-substituted thiazolo pyrrolidin-3-ylthio)carbapenem derivatives

Article abstract of DOI:10.1016/S0223-5234(02)01397-1

The synthesis of a new series of 1β-methylcarbapenems having the substituted thiazolopyrrolidine moiety is described. Their in vitro antibacterial activities against both Gram-positive including MRSA and Gram-negative bacteria were tested and the effect of substituent on the thiazole ring was investigated. A particular compound (28c) having 4′-amide substituted thiazole moiety showed the most potent antibacterial activity.

Full text of DOI:10.1016/S0223-5234(02)01397-1

European Journal of Medicinal Chemistry 37 (2002) 743ꢀ754
/
www.elsevier.com/locate/ejmech
Laboratory Note
Synthesis and antibacterial activity of 1b-methyl-2-(5-substituted
thiazolo pyrrolidin-3-ylthio)carbapenem derivatives
Chang-Hyun Oh a, Han-Won Cho a, Daejin Baek b, Jung-Hyuck Cho a,*
a Medicinal Chemistry Research Center, Korea Institute of Science and Technology, Seoul 130-650, Republic of Korea
b Department of Chemistry, Hanseo University, Seosan 356-706, Republic of Korea
Received 27 March 2002; received in revised form 4 June 2002; accepted 6 June 2002
Abstract
The synthesis of a new series of 1b-methylcarbapenems having the substituted thiazolopyrrolidine moiety is described. Their in
vitro antibacterial activities against both Gram-positive including MRSA and Gram-negative bacteria were tested and the effect of
substituent on the thiazole ring was investigated. A particular compound (28c) having 4?-amide substituted thiazole moiety showed
´
the most potent antibacterial activity. # 2002 Published by Editions scientifiques et me´dicales Elsevier SAS.
Keywords: 1b-Methylcarbapenem; Antibacterial activity; Substituent effect
1. Introduction
single side chain might lead to agents with a broader
spectrum of activity and anti-MRSA activity.
A number of carbapenem antibiotics, for example
imipenem, panipenem and meropenem, are currently in
clinical use due to their broad antibacterial spectra and
potent bactericidal effects [1]. However, a number of
problems still remain with these agents, in particular,
activity against resistant Gram-positive bacteria such as
methicillin-resistant Staphylococcus aureus (MRSA) and
the Gram-negative pathogen Pseudomonas aeruginosa,
is relatively weak. During the past decade, extensive
synthetic efforts have been made to confer anti-MRSA
activity on b-lactams such as a cephalosporin [2] or a
carbapenem [3]. As a result, some cephalosporin and
carbapenem derivatives with potent in vitro anti-MRSA
activity were identified by introducing hydrophobic
functional groups into the C-3 or C-7 side chain of the
cephalosporin nucleus or the C-2 side chain of the
carbapenem nucleus.
Previously, we reported that the carbapenem com-
pounds which have a pyrrolidine-3-ylthio group at the
C-2 position in the carbapenem skeleton are noted for
their broad and potent antibacterial activity, and a large
number of derivatives have been synthesised and
investigated [7ꢀ
/
11].
In this paper, we describe the synthesis and structureꢀ
/
activity relationships of the 1b-methylcarbapenems hav-
ing a 5?-substituted thiazolo pyrrolidine-3?-ylthio group
as C-2 side chain and our approach for improvement of
anti-MRSA and antibacterial activity of the carbape-
nems is discussed.
2. Results and discussion
2.1. Chemistry
From the literature of carbapenem antibiotics, espe-
cially the SAR related to meropenem [4,5] and panipe-
nem [6], the importance of a pyrrolidine ring for potent
activity and high PBP affinity were noted. Thus we
postulated that a combination of these two factors in a
Our general synthetic route leading to new carbape-
nems involved the preparation of appropriately pro-
tected thiols containing thiazole ring as a side chain and
subsequent coupling reaction with the carbapenem
diphenylphosphates, followed by deprotection of the
resulting protected carbapenems in a usual manner.
* Correspondence and reprints
E-mail address: choh@kist.re.kr (J.-H. Cho).
2-(4-Substituted
thiazole)pyrrolidine
derivatives
´
0223-5234/02/$ - see front matter # 2002 Published by Editions scientifiques et me´dicales Elsevier SAS.
PII: S 0 2 2 3 - 5 2 3 4 ( 0 2 ) 0 1 3 9 7 - 1

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C.-H. Oh et al. / European Journal of Medicinal Chemistry 37 (2002) 743ꢀ754
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Fig. 1. (a) Lawesson’s reagent, THF; (b) Ethyl bromopyruvate, EtOH; (c) 4N-NaOH, MeOH; (d) MsCl, TEA, CH2Cl2; (e) NaBH4, EtOH; (f)
AcSK, DMFꢀtouleneꢁ1:1; (g) 4N-NaOH, MeOH; (h) 28% NH4OH, MeOH.
/
/
containing the ester, hydroxy, amide, amine, aminosul-
fonmethyl and cyano group (25aꢀf) were prepared by
thioacetate in DMF and followed by hydrolysis of the
resulting acetylthio group with 4N-NaOH in methanol
led to the thiol compound (25a). Thiazole derivative 4
was reduced with sodium borohydride in EtOH to give
6. The 4?-ester substituted thiazole (3) was converted to
the amide 7 by aminolysis with aqueous ammonia in
MeOH. Compounds 25b and 25c were prepared from 6
and 7 by similiar methods to that described for the
preparation of 25a from 4 (Fig. 1).
/
the sequence shown in Figs. 1 and 2. The formation of
4?-substituted thiazole ring was accomplished by the
reaction of thioamide 2 with ethyl bromopyruvate in
EtOH solution. Debenzolylation of 3 with potassium
hydroxide gave the hydroxyl compound, which was
converted to the O-mesylated compound 4 by treatment
of mesyl chloride. Treatment of 4 with potassium
Fig. 2. (a) 4N-NaOH, MeOH; (b) TBSCl, imidazole, DMF; (c) NaBH4, EtOH; (d) MsCl, TEA, CH2Cl2; (e) potassium pthalimide, DMF; (f) N2H4×
H2O, MeOH; (g) MsCl, TEA, CH2Cl2; (h) PNZ-Cl TEA, CH2Cl2; (i) 1N-tetrabutylammonium fluoride, THF; (j) AcSK, DMFꢀtouleneꢁ1:1; (k)
4N-NaOH, MeOH (l) NaCN, DMSO.
/
/
/

C.-H. Oh et al. / European Journal of Medicinal Chemistry 37 (2002) 743ꢀ
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754
745
The protecting group of 3 converted into the
silyl group by the reaction with t-butyldimethyl-
silylchloride (TBSCl) and imidazole in DMF. The silyl
compound 8 was reduced with sodium borohydride in
EtOH and subsequently mesylated to give 9, which was
successfully converted into the amine 10 via phthalimide
derivative by the usual method. Sulfonylation of the
amine 10 with mesyl chloride proceeded to afford 11.
The treatment of the mesylated 9 with sodium cyanide in
DMSO gave the cyano substituted thiazole derivative
14.
2.2. Biological assay
2.2.1. Measurement of in vitro antibacterial activity
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 mLꢂ1
with the same broth and inoculated with an inoculating
device onto agar containing serial twofold dilutions of
the test compounds. Organisms were incubated at 37 8C
for 18ꢀ20 h. The MICs of a compound was defined as
/
the lowest concentration that visibly inhibited growth.
Deprotection of the silyl derivatives (11, 12, 14)
carried out with tetrabutylammonium fluoride in THF
2.2.2. Determination of susceptibility to renal
dehydropeptidase-I (DHP-I)
and the corresponding thiols (25dꢀf) were prepared by a
/
similar procedure of preparation of 25a (Fig. 2).
The relative hydrolysis rate of carbapenems by
porcine renal DHP-I was determined, taking the initial
hydrolysis rate of imipenem as 1.0. Partially purified
porcine DHP-I (final concentration, 0.3 U mLꢂ1) was
incubated with 50 mM carbapenem at 35 8C in 50 mM
MOPS buffer, pH 7.0. The initial hydrolysis rate was
monitored by the spectrophotometric method. One unit
of activity was defined as the amount of enzyme
hydrolyzing 1 mM of glycyldehydrophenylalanine per
min when the substrate, 50 mM, was incubated at 35 8C
in 50 mM MOPS buffer, pH 7.0.
The preparation of 2-methoxycarbonylmethylthiazole
(15) and 5-methylthiazole (18) were carried out using
methyl 4-chloroacetoacetate and methyl 2-chloroacetoa-
cetate by a similiar method for the preparation of 3,
respectively. Also the preparation of the corresponding
thiols (25gꢀ
(Fig. 3).
On the other hand, the pyrrolidine intermediate 20 for
one carbon homologated compound (nꢁ1) was ob-
-proline via several steps
/i) were obtained by above similar manners
/
tained from trans-hydroxy-
L
[11].
The other thiols (25jꢀ
methods as shown in Figs. 1 and 2 (Fig. 4). Finally, the
reaction of 26 [9] with thiols (25aꢀn) in the presence of
diisopropylethylamine provided the 2-substituted carba-
penem (27aꢀn). Deprotection of these compounds by
/
n) were prepared by similar
2.2.3. Antibacterial activity studies
The in vitro antibacterial activities of the new
/
carbapenems (28aꢀn) prepared above against Gram-
/
positive and negative bacteria including strains of
MRSA are listed in Table 1. For comparison, the
MIC values of imipenem, meropenem and vancomycin
/
catalytic hydrogenation gave the crude products, which
were purified by HP-20 column to give the pure
are also listed. All compounds (28aꢀ/n) displayed super-
carbapenems (28aꢀn) (Fig. 5).
/
ior or similar antibacterial activities against Gram-
Fig. 3. (a) Methyl-4-chloroacetoacetate, EtOH; (b) 28% NH4OH, MeOH; (c) MsCl, TEA, CH2Cl2; (d) AcSK, DMFꢀ
/
touleneꢁ1:1; (e) 4N-NaOH,
/
MeOH; (f) 4N-NaOH, MeOH; (g) NaBH4, EtOH; (h) methyl-2-chloroacetoacetate, EtOH.

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Fig. 4. (a) Lawesson’s reagent, THF; (b) ethyl bromopyruvate, EtOH; (c) methyl-4-chloroacetoacetate, EtOH; (d) 4N-NaOH, MeOH; (e) MsCl,
TEA, CH2Cl2; (f) 28% NH4OH, MeOH; (g) AcSK, DMFꢀ/touleneꢁ/1:1; (h) 4N-NaOH, MeOH; (i) NaBH4, EtOH.
positive to meropenem, and against Gram-negative
bacteria except P. aeruginosa to imipenem.
The amide substituted compounds (28c, 28m) showed
more improved stability to DHP-I than the correspond-
ing analogues (28a, b, l, n).
Comparing the compounds 28aꢀf having amide,
/
ester, hydroxy, amine, cyano group at C?-4 position of
thiazole showed slight differences in the antibacterial
activities against Gram-positive and -negative bacteria.
As expected, the 4?-amide substituted compound 28c
exhibited the most potent and well balanced activity.
The ester substituted compounds (28a, 28l) showed
better antibacterial activities especially against Gram-
positive bacteria than the corresponding analogues
3. Experimental
Melting point (m.p.): Thomas Hoover apparatus,
uncorrected. UV spectra: Hewlett-Packard 8451A
UVꢀ
/
vis spectrophotometer. IR spectra: PerkinꢀElmer
/
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.
(28bꢀe).
/
As an extent of alkyl group in the thiazole ring
increased, antibacterial activity generally decreased
against Gram-positive and -negative bacteria including
strains of MRSA, as shown in compounds (28b, c vs.
28h, g). Also introduction of a methyl group in the
thiazole ring 28i significantly lowered the antibacterial
activity compared to compound 28b. On the other hand,
3.1. (2S,4R)-4-Benzoyloxy-2-thiocarbamoyl-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (2)
Compound 1 [11] (7.02 g, 17.0 mmol) and Lawesson’s
reagent (4.10 g, 10.0 mmol) were dissolved in THF (50
mL) and the solution was heated at reflux for 2 h.
Evaporation of the resulting solution in vacuo gave a
crude residue, which was purified by silica gel column
chromatography to give 2 (6.91 g, 94.7%) as a pale
comparison with 28aꢀ
/
c and 28jꢀn shows that introduct-
/
ion of carbon between pyrrolidine and thiazole does not
enhance antibacterial activities but showed high stability
to renal DHP-I. From these observations, the length of
the spacer part seems to play important roles improving
stability while decreasing antibacterial activity.
1
yellow solid. H-NMR (CDCl3): d 2.47 (bs, 1H), 2.72
(bs, 1H), 3.86 (bs, 1H), 4.01 (bs, 1H), 4.55 (bs, 2H), 5.05
Fig. 5. (a) N,N-Diisopropylethylamine, CH3CN; (b) H2, Pdꢀ
/
C, THFꢀH2O.
/

Table 1
In vitro antibacterial activity (MIC, mg mLꢂ1) and DHP-I stability of the carbapenem derivatives
Strains
28a
28b
28c
28d
28e
28f
28g
28h
0.02
28i
0.02
28j
0.02
28k
0.01
28l
28m
28n
IPM
MPM
VCM
S. pyogenes 308A
S. pyogenes 77A
S. aureus SG511
S. aureus 285
B0.01
B0.01
0.03
0.03
0.10
0.40
6.20
0.01
0.05
1.56
0.05
0.03
0.01
0.98
B0.01
0.01
0.03
0.05
0.10
0.40
3.10
0.01
0.01
1.56
0.02
0.05
0.01
1.11
B0.01
B0.01
0.03
0.05
0.10
0.20
6.20
0.01
0.01
1.56
0.02
0.03
0.01
1.59
B0.01
0.01
0.05
0.10
0.20
0.40
6.20
0.05
0.05
3.10
0.10
0.10
0.05
1.27
B0.01
0.01
0.05
0.10
0.20
0.40
6.20
0.03
0.03
12.5
0.05
0.05
0.02
1.05
B0.01
0.01
0.05
0.10
0.20
0.40
12.5
0.01
0.03
6.10
0.03
0.05
0.01
1.61
0.10
0.10
0.05
0.10
0.80
0.40
B0.01
B0.01
0.03
0.03
12.5
6.20
12.5
0.03
0.03
1.56
0.05
0.05
0.03
1.71
B0.01
B0.01
0.03
0.05
25.0
0.40
3.10
0.03
0.03
1.56
0.05
0.05
0.03
2.05
0.01
0.01
B0.01
B0.01
0.01
ꢀ/
ꢀ/
ꢀ/
ꢀ/
0.80
0.80
0.40
0.02
0.05
0.10
3.10
0.40
0.02
0.10
0.20
0.02
0.20
0.20
0.01
0.10
0.20
B0.01
0.10
0.10
0.05 0.01
0.10 0.01
a
S. aureus SNU5
S. aureus SNU12
S. aureus SNU16
6.20 12.5
0.80 1.56
12.5 25.0
0.10
0.10
12.5
1.56
25.0
12.5
0.80
12.5
ꢀ/
ꢀ/
ꢀ/
ꢀ/
ꢀ/
ꢀ/
0.03
0.03
0.20
0.03
0.05
0.03
1.00
a
a
3.10 25.0
Escherichia coli DC2
E. Coli TEM
0.03
0.05
6.10
0.03
0.05
0.01
0.93
0.03
0.05
0.03
0.05
0.20
0.20
0.05 0.40
0.10 0.20
6.20 0.80
0.05 0.80
0.05 0.10
0.05 0.10
1.33 0.18
ꢀ/
ꢀ/
ꢀ/
ꢀ/
ꢀ/
ꢀ/
ꢀ/
P. aeruginosa 1592E
S. typhimurium
K. aerogenes 1522E
E. cloacae 1321E
DHP-1
6.10 12.5
6.10 12.5
0.05
0.03
0.03
0.90
0.10
0.40
0.40
0.20
1.54
0.20
0.10
0.05
1.57
0.20
0.10
1.25
a
Methicillin resistant. IPM, imipenem; MPM, meropenem; VCM, vancomycin.

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C.-H. Oh et al. / European Journal of Medicinal Chemistry 37 (2002) 743ꢀ754
/
and 5.32 (2H, s and dd, Jꢁ
7.49 (m, 4H), 7.64 (d, 1H, Jꢁ
7.1 Hz), 8.11 (d, 2H, Jꢁ7.1 Hz).
/
12.6 Hz), 5.80, 6.12 (bs, 2H),
washed with EtOAc (20ꢃ2 mL). The combined solvent
was washed with brine and dried over anhydrous
Na2SO4. Removal of the solvent gave a crude residue,
/
/
7.1 Hz), 7.94 (d, 2H, Jꢁ
/
/
which was chromatographed on silica gel using EtOAcꢀ
/
3.2. (2S,4R)-4-Benzoyloxy-2-(4-
ethoxycarbonythiazole-2-yl)-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (3)
n-C6H14 (1:1) to give 5 (0.47 g, 85.0%) as a pale yellow
1
oil. H-NMR (CDCl3): d 1.34 (t, 3H, Jꢁ
(bs, 1H), 2.31 (s, 3H), 2.87 (bs, 1H), 3.98ꢀ4.07 (bs, 2H),
4.11 (q, 2H, Jꢁ7.7 Hz), 4.65 (bs, 1H), 5.15 (bs, 1H),
5.31 (bs, 2H), 7.05 (s, 1H), 7.35 (d, 1H, Jꢁ7.5 Hz), 7.60
(d, 1H, Jꢁ7.5 Hz), 7.99 (d, 1H, Jꢁ7.5 Hz), 8.09 (d,
1H, Jꢁ7.5 Hz).
/7.7 Hz), 2.18
/
/
To a stirred solution of 2 (4.29 g, 10.0 mmol) in EtOH
(60 mL) was added dropwise ethyl bromopyruvate (1.80
mL, 13.0 mol) and was stirred for 20 h at room
temperature (r.t.). The resulting solution was evaporated
and diluted with EtOAc, and washed with brine. The
organic 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 3 (4.69 g, 89.2%) as a pale
/
/
/
/
3.5. (2S,4S)-2-(4-Ethoxycarbonylthiazole-2-yl)-4-
mercapto-1-(p-nitrobenzyloxycarbonyl)pyrrolidine
(25a)
To a solution of 5 (1.11 g, 2.32 mmol) in MeOH (15
mL) was added 0.58 mL of 4N-NaOH at ice bath. After
stirring for 20 min at the same temperature, 0.58 mL of
4N-HCl was added to this solution and diluted with
EtOAc, washed with water, brine and dried over
anhydrous Na2SO4. The solvent was evaporated in
yellow oil. 1H-NMR (CDCl3): d 1.43 (t, 3H, Jꢁ
2.75ꢀ2.81 (bs, 2H), 3.98ꢀ4.07 (bs, 2H), 4.17 (q, 2H, Jꢁ
7.9 Hz), 4.95 (bs, 1H), 5.15 (bs, 1H), 5.61 (bs, 2H), 7.27
(s, 1H), 7.49 (t, 3H, Jꢁ8.5 Hz), 7.66 (t, 1H, Jꢁ8.5 Hz),
7.96 (d, 2H, Jꢁ8.5 Hz), 8.11 (d, 2H, Jꢁ8.5 Hz).
/
7.9 Hz),
/
/
/
/
/
/
/
1
vacuo to give 25a (0.96 g, 94.9%) as a yellow oil. H-
3.3. (2S,4R)-2-(4-Ethoxycarbonythiazole-2-yl)-4-
mesyloxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (4)
NMR (CDCl3): d 1.34 (t, 3H, Jꢁ
2.77 (bs, 1H), 3.89ꢀ4.08 (bs, 2H), 4.14 (q, 2H, Jꢁ
Hz), 5.15ꢀ5.26 (bs, 2H), 5.45 (bs, 2H), 7.01 (s, 1H), 7.35
(d, 1H, Jꢁ7.5 Hz), 7.60 (d, 1H, Jꢁ7.5 Hz), 7.95 (d,
1H, Jꢁ7.5 Hz), 8.11 (d, 1H, Jꢁ7.5 Hz).
/7.3 Hz), 2.08 (bs, 1H),
/
/7.3
/
To a solution of 3 (5.50 g, 10.5 mmol) in MeOH (20
mL) was added 0.59 g of KOH (10.5 mmol) at ice bath.
After stirring for 2 h, the reaction mixture was
neutralised with 4N-HCl and was diluted with EtOAc,
washed with water, brine and dried over anhydrous
Na2SO4. The solvent was evaporated in vacuo to give a
yellow oil. A solution of above and Et3N (1.41 mL, 10.5
mmol) in dry CH2Cl2 was cooled to 0 8C under
nitrogen and treated with methanesulfonyl chloride
(1.20 g, 10.5 mmol). The mixture was stirred at 0 8C
for 1 h, diluted with EtOAc (50 mL), and washed with
10% NaHCO3 and brine. The organic layer was dried
over anhydrous Na2SO4. Evaporation of the solvent in
vacuo gave a crude residue, which was purified by silica
/
/
/
/
3.6. (2S,4R)-2-(4-Hydroxymethylthiazole-2-yl)-4-
mesyloxy-1-(p-nitrobenzyloxycarbonyl)pyrroli dine (6)
To a solution of 4 (2.40 g, 4.80 mmol) in EtOH (50
mL) was added slowly NaBH4 (0.54 g 14.3 mmol) at
0 8C. After 5 h, the mixture was diluted with H2O (20
mL), 1N-HCl and EtOAc (50 mL). The organic layer
was dried over anhydrous Na2SO4, concentrated, and
the resulting residue was purified by silica gel column
chromatography to give 6 (1.48 g, 67.3%) as a pale
1
yellow oil. H-NMR (CDCl3): d 2.27 (bs, 1H), 2.85 (bs,
1H), 3.05 (s, 3H), 3.50 (s, 2H), 3.88 (bs, 1H), 4.05 (bs,
gel column chromatography to give 4 (4.61 g, 87.9%) as
1
a pale yellow oil. H-NMR (CDCl3): d 1.34 (t, 3H, Jꢁ
/
1H), 4.81 (bs, 1H), 5.19ꢀ
7.05 (s, 1H), 7.25 (d, 1H, Jꢁ
7.2 Hz), 8.12 (d, 1H, Jꢁ7.2 Hz), 8.24 (d, 1H, Jꢁ
Hz).
/
5.26 (bs, 2H), 5.45 (bs, 1H),
7.2 Hz), 7.65 (d, 1H, Jꢁ
7.2
7.7 Hz), 2.25 (bs, 1H), 2.81 (bs, 1H), 3.01 (s, 3H), 3.98ꢀ
4.07 (bs, 2H), 4.11 (q, 2H, Jꢁ7.7 Hz), 4.81 (bs, 1H),
5.15 (bs, 1H), 5.41 (bs, 2H), 7.05 (s, 1H), 7.35 (d, 1H,
Jꢁ7.5 Hz), 7.60 (d, 1H, Jꢁ7.5 Hz), 7.96 (d, 1H, Jꢁ7.5
Hz), 8.11 (d, 1H, Jꢁ7.5 Hz).
/
/
/
/
/
/
/
/
/
/
3.7. (2S,4S)-2-(4-Hydroxymethylthiazole-2-yl)-4-
mercapto-1-(p-nitrobenzyloxycarbonyl)pyrrolidine
(25b)
3.4. (2S,4S)-4-Acetylthio-2-(4-ethoxycarbonythiazole-
2-yl)-1-(p-nitrobenzyloxycarbonyl)pyrroli dine (5)
A mixture of 4 (0.58 g, 1.15 mmol) and potassium
thioacetate (0.39 g, 3.45 mmol) in DMF (20 mL) and
C6H5CH3 (20 mL) was stirred at 70 8C for 3 h under N2
gas. After cooling, the reaction mixture was diluted with
EtOAc (50 mL), water (50 mL) and the aq. layer was
Compound 25b was prepared from 6 by a similiar
method to that described for the preparation of 25a
1
from 4. H-NMR (CDCl3): d 2.20 (bs, 1H), 2.89 (bs,
1H), 3.51 (s, 2H), 3.88 (bs, 1H), 4.00 (bs, 1H), 4.77 (bs,
1H), 5.16ꢀ5.28 (bs, 2H), 5.45 (bs, 1H), 7.05 (s, 1H), 7.25
/

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749
(d, 1H, Jꢁ
/
7.1 Hz), 7.68 (d, 1H, Jꢁ
/
7.1 Hz), 8.10 (d,
1H), 7.11 (s, 1H), 7.46 (d, 2H, Jꢁ
/
7.2 Hz), 8.16 (d, 2H,
1H, Jꢁ7.1 Hz), 8.22 (d, 1H, Jꢁ
/
/7.1 Hz).
Jꢁ 7.2 Hz).
/
3.8. (2S,4R)-2-(4-Carbamoylthiazole-2-yl)-4-hydroxy-
1-(p-nitrobenzyloxycarbonyl)pyrrolidine (7)
3.11. (2S,4R)-4-(t-Butyldimethylsilanyloxy)-2-(4-
mesyloxymethylthiazole-2-yl)-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (9)
To a stirred solution of 3 (1.46 g, 2.78 mmol) in
MeOH (20 mL) was added NaOH (28%, 20 mL) and
was stirred for 20 h at r.t. The mixture was neutralised
with 6N-HCl, diluted with EtOAc (50 mL), and washed
with brine. The organic layer was dried over anhydrous
Na2SO4, which was purified by silica gel column
chromatography to give 7 (0.85 g, 78.1%) as a pale
To a solution of 8 (5.71 g, 10.0 mmol) in EtOH (80
mL) was added slowly NaBH4 (1.14g 30.0 mmol) at
0 8C. After 6 h, the mixture was diluted with H2O (30
mL), 1N-HCl and EtOAc (80 mL). The organic layer
was concentrated in vacuo to give a residue, which was
used without further purification. A solution of above
and Et3N (1.21 mL, 9.0 mmol) in dry CH2Cl2 was
cooled to 5 8C under nitrogen and treated with
methanesulfonyl chloride (1.03 g, 9.0 mmol). The
mixture was stirred at 0 8C for 1 h, diluted with EtOAc
(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
residue, which was purified by silica gel column
chromatography to give 9 (4.11 g, 71.9%) as a pale
1
yellow oil. H-NMR (CDCl3): d 2.50 (bs, 1/2H), 2.75
(bs, 1H), 2.88 (bs, 1/2H), 3.88 (bs, 1H), 4.02 (bs, 1H),
5.19ꢀ
7.04 (s, 1H), 7.25 (d, 1H, Jꢁ
7.4 Hz), 8.01 (d, 1H, Jꢁ7.4 Hz), 8.12 (d, 1H, Jꢁ
Hz).
/
5.31 (bs, 2H), 5.45 (bs, 2H), 6.50ꢀ
7.4 Hz), 7.63 (d, 1H, Jꢁ
7.4
/
6.62 (2bs, 2H),
/
/
/
/
3.9. (2S,4S)-2-(4-Carbamoylthiazole-2-yl)-4-mercapto-
1-(p-nitrobenzyloxycarbonyl)pyrrolidine (25c)
1
Compound 25c was prepared from 7 by a similiar
method to that described for the preparation of 25a. 1H-
NMR (CDCl3): d 2.20 (bs, 1H), 2.88 (bs, 1H), 3.86 (bs,
yellow oil. H-NMR (CDCl3): d 0.01 (s, 6H), 0.99 (s,
9H), 2.25 (bs, 1H), 2.81 (bs, 1H), 3.03 (s, 3H), 3.37 (s,
2H), 3.88ꢀ
dd, 2H, Jꢁ
2H, Jꢁ 7.2 Hz), 8.18 (d, 2H, Jꢁ
/
4.03 (bs, 2H), 4.93 (bs, 1H), 5.15ꢀ
7.9 Hz), 5.51 (bs, 1H), 7.11 (s, 1H), 7.49 (d,
7.2 Hz).
/
5.30 (s and
1H), 4.04 (bs, 1H), 5.19ꢀ
6.50ꢀ6.62 (2bs, 2H), 7.01 (s, 1H), 7.23 (d, 1H, Jꢁ
Hz), 7.66 (d, 1H, Jꢁ7.3 Hz), 8.06 (d, 1H, Jꢁ7.4 Hz),
8.14 (d, 1H, Jꢁ7.4 Hz).
/
5.31 (bs, 2H), 5.49 (bs, 2H),
/
/
/
7.3
/
/
/
/
/
3.12. (2S,4R)-2-(4-Aminomethylthiazole-2-yl)-4-(t-
butyldimethylsilanyloxy)-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (10)
3.10. (2S,4R)-4-(t-Butyldimethylsilanyloxy)-2-(4-
ethoxycarbonylthiazole-2-yl)-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (8)
A mixture of 9 (2.31 g, 4.01 mmol) and potassium
phthalimide (1.48 g, 8.02 mmol) in DMF (30 mL) was
heated at 100 8C for 1 h. The reaction mixture was
poured into ice water and extracted with EtOAc. The
residue was purified by silica gel column chromatogra-
To a solution of 3 (5.0 g, 9.52 mmol) in MeOH (20
mL) was added 0.53 g of KOH (9.52 mmol) at ice bath.
After stirring for 2 h, the reaction mixture was
neutralised with 4N-HCl and was diluted with EtOAc,
washed with water, brine and dried over anhydrous
Na2SO4. The solvent was evaporated in vacuo to give a
yellow oil. To mixture of above compound and imida-
zole (13.26 g, 22.5 mmol) in DMF (40 mL) was added
TBSCl (13.56 g, 9.0 mmol) and stirred at r.t. for 15 h
under N2 gas. The reaction mixture was diluted with
EtOAc (50 mL), water (50 mL) and the aqueous layer
phy (C6H5CH3ꢀ
/
EtOAcꢁ8:1) to give phthalimidate
/
compound. To a solution of above compound in a
mixture of CH2Cl2 (10 mL) and MeOH (30 mL),
hydrazine hydrate (0.40 g, 8.02 mmol) was added. After
being heated at 60 8C for 5 h, the reaction mixture was
evaporated in vacuo to dryness. The residue was
dissolved in CH2Cl2 and the resulting precipitates were
filtered off. The filtrate was washed with water, dried
over MgSO4 and evaporated. The residue was purified
by silica gel column chromatography to give 10 (1.36 g,
69.1%) as a pale yellow oil. 1H-NMR (CDCl3): d 0.01 (s,
was washed with EtOAc (30ꢃ/2 mL). The combined
solvent was washed with water (30 mLꢃ/3), brine and
dried over anhydrous Na2SO4. Removal of the solvent
gave a crude residue, which was chromatographed on
silica gel using EtOAcꢀ
77.1%) as a pale yellow oil. 1H-NMR (CDCl3): d 0.01 (s,
6H), 0.99 (s, 9H), 1.34 (t, 3H, Jꢁ7.0 Hz), 2.75ꢀ2.81 (bs,
2H), 3.88ꢀ4.07 (bs, 2H), 4.12 (q, 2H, Jꢁ7.0 Hz), 4.95
(bs, 1H), 5.15ꢀ5.30 (s and dd, 2H, Jꢁ 7.9 Hz), 5.61 (bs,
/n-C6H14 (1:1) to give 8 (3.93 g,
6H), 0.99 (s, 9H), 2.25 (bs, 1H), 2.31 (bs, 1H), 3.68ꢀ
(bs, 2H), 4.53 (bs, 3H), 5.19ꢀ5.33 (s and dd, 2H, Jꢁ
Hz), 5.51 (bs, 1H), 7.01 (s, 1H), 7.51 (d, 2H, Jꢁ 7.1 Hz),
8.29 (d, 2H, Jꢁ 7.1 Hz).
/3.86
/
/
7.5
/
/
/
/
/
/
/
/

750
C.-H. Oh et al. / European Journal of Medicinal Chemistry 37 (2002) 743ꢀ754
/
3.13. (2S,4R)-4-(t-Butyldimethylsilanyloxy)-2-(4-
methanesulfonylaminomethylthiazole-2-yl)-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (11)
solvent in vacuo gave a crude residue, which was
purified by silica gel column chromatography to give
13 (0.80 g, 75.8%) as a pale yellow oil. 1H-NMR
(CDCl3): d 2.21 (bs, 1H), 2.35 (bs, 1H), 3.01 (s, 3H),
A solution of 10 (2.0 g, 4.05 mmol) and Et3N (0.65
mL, 4.86 mmol) in dry CH2Cl2 was cooled to 0 8C
under nitrogen and treated with methanesulfonyl chlo-
ride (0.56 g, 4.86 mmol). The mixture was stirred at
0 8C for 1 h, diluted with EtOAc (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 residue, which was purified by silica
gel column chromatography to give 11 (2.10 g, 91.1%) as
a pale yellow oil. 1H-NMR (CDCl3): d 0.01 (s, 6H), 0.99
3.68ꢀ
dd, 2H, Jꢁ
1H, Jꢁ 6.8 Hz), 7.53 (d, 3H, Jꢁ
Jꢁ 6.8 Hz), 8.25 (d, 3H, Jꢁ 6.8 Hz).
/
3.90 (bs, 2H), 4.45ꢀ
7.5 Hz), 5.90 (bs, 1H), 7.05 (s, 1H), 7.13 (d,
6.8 Hz), 8.05 (d, 1H,
/
4.56 (bs, 3H), 5.19ꢀ5.33 (s and
/
/
/
/
/
/
3.16. (2S,4R)-4-(t-Butyldimethylsilanyloxy)-2-(4-
cyanomethylthiazole-2-yl)-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (14)
(s, 9H), 2.28ꢀ
3.88 (bs, 1H), 4.11 (bs, 1H), 4.31 (bs, 1H), 4.45 (s, 2H),
5.23ꢀ5.38 (s and dd, 2H, Jꢁ 7.5 Hz), 5.88 (bs, 1H), 7.15
(s, 1H), 7.35 (d, 1H, Jꢁ 7.1 Hz), 7.58 (d, 1H, Jꢁ 7.1
Hz), 8.03 (d, 1H, Jꢁ 7.1 Hz), 8.28 (d, 1H, Jꢁ 7.1 Hz).
/
2.32 (bs, 2H), 2.98 (bs, 3H), 3.68 (m, 1H),
A mixture of 9 (1.50 g, 2.62 mmol) and sodium
cyanide (0.39 g, 7.86 mmol) in DMSO (20 mL) was
stirred at 70 8C for 8 h under N2 gas. After cooling, the
reaction mixture was diluted with EtOAc (50 mL), water
(50 mL) and the aqueous layer was washed with EtOAc
/
/
/
/
/
/
(20ꢃ2 mL). The combined solvent was washed with
/
3.14. (2S,4R)-4-(t-Butyldimethylsilanyloxy)-2-[4-(p-
nitrobenzyloxycarbonylaminomethylthizole-2-yl)]-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (12)
brine and dried over anhydrous Na2SO4. Removal of
the solvent gave a crude residue, which was chromato-
graphed on silica gel using EtOAcꢀ
14 (1.03 g, 78.5%) as a pale yellow oil. 1H-NMR
(CDCl3): d 0.01 (s, 6H), 0.99 (s, 9H), 2.28ꢀ2.32 (bs,
2H), 3.68 (m, 1H), 3.88 (bs, 1H), 4.11 (bs, 1H), 4.17ꢀ
4.31 (bs, 3H), 5.23ꢀ5.38 (s and dd, 2H, Jꢁ 7.5 Hz), 7.11
(s, 1H), 7.35 (d, 1H, Jꢁ 7.0 Hz), 7.52 (d, 1H, Jꢁ
Hz), 8.01 (d, 1H, Jꢁ 7.0 Hz), 8.21 (d, 1H, Jꢁ
/n-C6H14 (1:2) to give
A solution of 10 (1.42 g, 2.88 mmol) and Et3N (0.46
mL, 3.46 mmol) in dry CH2Cl2 was cooled to 0 8C
under nitrogen and treated with p-nitrobenzylchloro-
formate (0.75 g, 3.46 mmol). The mixture was stirred at
0 8C for 1 h, diluted with EtOAc (50 mL), and washed
with 10% NaHCO3 and brine. The organic 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
12 (1.82 g, 94.2%) as a pale yellow oil. 1H-NMR
(CDCl3): d 0.01 (s, 6H), 0.99 (s, 9H), 2.25 (bs, 1H),
/
/
/
/
/
/
7.0
/
/
7.0 Hz).
3.17. (2S,4S)-4-Mercapto-2-[4-(p-
nitrobenzyloxycarbonylaminomethyl)thiazole-2-yl)]-1-
(p-nitrobenzyloxycarbonyl)pyrrolidine (25d)
2.32 (bs, 1H), 3.68ꢀ
5.33 (s and dd, 2H, Jꢁ
1H), 7.15 (d, 1H, Jꢁ 7.1 Hz), 7.55 (d, 3H, Jꢁ
8.07 (d, 1H, Jꢁ 7.1 Hz), 8.25 (d, 3H, Jꢁ 7.1 Hz).
/
3.88 (bs, 2H), 4.53 (bs, 3H), 5.19ꢀ
7.5 Hz), 5.51 (bs, 1H), 7.01 (s,
7.1 Hz),
/
Compound 25d was prepared from 13 by a similiar
method to that described for the preparation of 25a
/
1
from 4. H-NMR (CDCl3): d 2.09 (bs, 1H), 2.85 (bs,
/
/
/
/
1H), 3.68ꢀ
(s and dd, 2H, Jꢁ
7.13 (d, 1H, Jꢁ 6.9 Hz), 7.55 (d, 3H, Jꢁ
(d, 1H, Jꢁ 6.9 Hz), 8.28 (d, 3H, Jꢁ 6.8 Hz).
/
3.90 (bs, 2H), 4.45ꢀ
7.9 Hz), 5.90 (bs, 1H), 7.09 (s, 1H),
6.8 Hz), 8.08
/
4.56 (bs, 3H), 5.20ꢀ5.35
/
/
3.15. (2S,4R)-4-Mesyloxy-2-[4-(p-
/
/
nitrobenzyloxycarbonylaminomethyl)thiazole-2-yl)]-1-
/
/
(p-nitrobenzyloxycarbonyl)pyrrolidine (13)
To a solution of 12 (1.13 g, 1.66 mmol) in THF (30
mL) was added slowly a solution of 1 M nBu4NF (2.49
mL, 2.49 mmol) in THF, and then was stirred for 2 h at
r.t. The solvent was concentrated in vacuo to give a
residue, which was used without further purification. A
solution of above (0.73 g, 1.57 mmol) and Et3N (0.23
mL, 1.73 mmol) in dry CH2Cl2 was cooled to 5 8C
under nitrogen and treated with methanesulfonyl chlo-
ride (0.20 g, 1.73 mmol). The mixture was stirred at
0 8C for 1 h, diluted with EtOAc (50 mL), and washed
with 10% NaHCO3 and brine. The organic layer was
dried over anhydrous Na2SO4. Evaporation of the
3.18. (2S,4S)-4-Mercapto-2-(4-
methanesulfonylaminomethylthiazole-2-yl)-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (25e)
Compound 25e was prepared from 11 by a similiar
method to that described for the preparation of 25d
1
from 12. H-NMR (CDCl3): d 2.28ꢀ
/2.32 (bs, 1H), 3.68
(m, 1H), 3.88 (bs, 1H), 4.11 (bs, 1H), 4.31 (bs, 1H), 4.45
(s, 2H), 5.22ꢀ5.38 (s and dd, 2H, Jꢁ 7.5 Hz), 5.50 (bs,
1H), 7.11 (s, 1H), 7.30 (d, 1H, Jꢁ 7.4 Hz), 7.59 (d, 1H,
Jꢁ 7.4 Hz), 8.09 (d, 1H, Jꢁ 7.4 Hz), 8.28 (d, 1H, Jꢁ
7.4 Hz).
/
/
/
/
/
/

C.-H. Oh et al. / European Journal of Medicinal Chemistry 37 (2002) 743ꢀ
/
754
751
3.19. (2S,4S)-2-(4-Cyanomethylthiazole-2-yl)-4-
mercapto-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (25f)
3.23. (2S,4R)-2-[4-(2-Hydroxyethyl)thiazole-2-yl]-4-
mesyloxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (17)
Compound 25f was prepared from 14 by a similiar
method to that described for the preparation of 25d
Compound 17 was prepared from 15 by a similiar
method to that described for the preparation of 6 from
1
1
from 12. H-NMR (CDCl3): d 2.28ꢀ/2.32 (bs, 1H), 3.68
3. H-NMR (CDCl3): d 2.18 (bs, 1H), 2.70ꢀ
/
2.89 (bs,
4.01 (bs, 4H), 4.95 (bs, 1H),
5.38 (bs and s, 2H), 5.60 (bs, 1H), 7.03 (s, 1H), 7.51
(d, 2H, Jꢁ7.4 Hz), 8.12 (d, 2H, Jꢁ7.4 Hz).
(m, 1H), 3.88 (bs, 1H), 4.11 (bs, 1H), 4.31 (bs, 1H), 4.45
(s, 2H), 5.22ꢀ5.38 (s and dd, 2H, Jꢁ 7.5 Hz), 5.50 (bs,
1H), 7.11 (s, 1H), 7.30 (d, 1H, Jꢁ 7.4 Hz), 7.59 (d, 1H,
Jꢁ 7.4 Hz), 8.09 (d, 1H, Jꢁ 7.4 Hz), 8.28 (d, 1H, Jꢁ
7.4 Hz).
3H), 3.01 (s, 3H), 3.66ꢀ
/
/
/
5.15ꢀ
/
/
/
/
/
/
/
3.24. (2S,4S)-2-[4-(2-Hydroxyethyl)thiazole-2-yl]-4-
mercapto-1-(p-nitrobenzyloxycarbonyl)pyrrolidine
(24h)
3.20. (2S,4R)-4-Benzoyloxy-2-(4-
methoxycarbonylmethylthiazole-2-yl)-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (15)
Compound 24h was prepared from 17 by a similiar
method to that described for the preparation of 25b. 1H-
NMR (CDCl3): d 2.21 (bs, 1H), 2.69ꢀ
3.69ꢀ4.05 (m, 4H), 4.95 (bs, 1H), 5.15ꢀ5.38 (bs and s,
2H), 5.63 (bs, 1H), 7.01 (s, 1H), 7.55 (d, 2H, Jꢁ7.4 Hz),
8.11 (d, 2H, Jꢁ7.4 Hz).
/
2.85 (bs, 3H),
To a stirred solution of 2 (5.0 g, 11.64 mmol) in EtOH
(70 mL) was added dropwise methyl 4-chloroacetoace-
tate (1.64 mL, 13.97 mmol) and was stirred for 20 h at
reflux. The resulting solution was evaporated and
diluted with EtOAc, and washed with brine. The organic
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 15
/
/
/
/
3.25. (2S,4R)-4-Benzoyloxy-2-(4-methoxycarbonyl-5-
methylthiazole-2-yl)-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (18)
1
(4.78 g, 78.2%) as a pale yellow oil. H-NMR (CDCl3):
The compound 18 was achieved using methyl 2-
chloroacetoacetate by the same method as described
for the preparation of 15 (84.5%). 1H-NMR (CDCl3): d
d 2.75ꢀ
4.95 (bs, 1H), 5.15ꢀ
7.05 (s, 1H), 7.25 (t, 2H, Jꢁ
Hz), 7.66 (t, 1H, Jꢁ7.8 Hz), 7.78 (m, 3H), 8.13 (d, 1H,
Jꢁ7.9 Hz), 8.30 (d, 1H, Jꢁ7.8 Hz).
/
2.85 (bs, 2H), 3.55 (s, 3H), 3.64ꢀ
5.38 (bs and s, 2H), 5.63 (bs, 1H),
8.1 Hz), 7.49 (d, 1H, Jꢁ7.9
/
4.01 (bs, 4H),
/
/
/
2.51 (s, 3H), 2.75ꢀ
(bs, 2H), 4.95 (bs, 1H), 5.15ꢀ
(bs, 1H), 7.27 (t, 2H, Jꢁ8.1 Hz), 7.49 (d, 1H, Jꢁ
Hz), 7.66 (t, 1H, Jꢁ8.1 Hz), 7.78 (m, 3H), 8.11 (d, 1H,
Jꢁ8.1 Hz), 8.31 (d, 1H, Jꢁ8.1 Hz).
/
2.85 (bs, 2H), 3.55 (s, 3H), 3.88ꢀ
5.40 (bs and s, 2H), 5.69
8.1
/
4.01
/
/
/
/
/
/
/
/
/
3.21. (2S,4R)-2-(4-Carbamoylmethylthiazole-2-yl)-4-
hydroxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (16)
3.26. (2S,4R)-2-(4-Hydroxymethyl-5-methylthiazole-2-
yl)-4-mesyloxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine
(19)
Compound 16 was prepared from 15 by a similiar
method to that described for the preparation of 7 from 3
1
(79.9%). H-NMR (CDCl3): d 2.35 (bs, 1/2H), 2.72 (bs,
Compound 19 was prepared from 18 by a similiar
method to that described for the preparation of 6 from
1H), 2.88 (bs, 1/2H), 3.81ꢀ
5.18ꢀ5.34 (bs, 2H), 5.45 (bs, 2H), 6.50ꢀ
7.01 (s, 1H), 7.29 (d, 1H, Jꢁ7.4 Hz), 7.62 (d, 1H, Jꢁ
7.4 Hz), 8.02 (d, 1H, Jꢁ7.4 Hz), 8.15 (d, 1H, Jꢁ7.4
Hz).
/
4.05 (bs, 3H), 4.02 (bs, 1H),
/
/6.62 (2bs, 2H),
3. 1H-NMR (CDCl3): d 2.39 (s, 3H), 2.75ꢀ
/
2.89 (bs, 2H),
4.01 (bs, 3H), 4.51 (bs, 1H), 5.02 (bs,
5.40 (bs and s, 2H), 7.48 (d, 2H, Jꢁ7.8 Hz),
8.23 (d, 2H, Jꢁ7.8 Hz).
/
/
3.02 (s, 3H), 3.88ꢀ
/
/
/
2H), 5.15ꢀ
/
/
/
3.22. (2S,4S)-2-(4-Carbomoylmethylthiazole-2-yl)-4-
mercapto-1-(p-nitrobenzyloxycarbonyl)pyrrolidine
(25g)
3.27. (2S,4S)-2-(4-Hydroxymethyl-5-methylthiazole-2-
yl)-4-mercaptan-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (25i)
Compound 25g was prepared from 16 by a similiar
method to that described for the preparation of 25c. 1H-
Compound 25i was prepared from 19 by a similiar
method to that described for the preparation of 25b. 1H-
NMR (CDCl3): d 2.25 (bs, 1H), 2.85 (bs, 1H), 3.64ꢀ
(bs, 4H), 4.95 (bs, 1H), 5.15ꢀ5.38 (bs and s, 2H), 5.63
(bs, 1H), 5.99 (bs, 1H), 6.17 (bs, 1H), 7.02 (s, 1H), 7.46
(d, 2H, Jꢁ7.9 Hz), 8.13 (d, 2H, Jꢁ7.9 Hz).
/
4.01
NMR (CDCl3): d 2.35 (s, 3H), 2.75ꢀ
3.88ꢀ4.01 (bs, 3H), 4.55 (bs, 1H), 5.09 (bs, 2H), 5.15ꢀ
5.40 (bs and s, 2H), 7.49 (d, 2H, Jꢁ7.8 Hz), 8.23 (d, 2H,
Jꢁ7.8 Hz).
/
2.85 (bs, 2H),
/
/
/
/
/
/
/

752
C.-H. Oh et al. / European Journal of Medicinal Chemistry 37 (2002) 743ꢀ754
/
3.28. (2S,4R)-4-Benzoyloxy-2-thiocarbamoylmethyl-1-
(p-nitrobenzyloxycarbonyl)pyrrolidine (21)
(bs and s, 2H), 5.45 (bs, 1H), 7.03 (s, 1H), 7.50 (d, 2H,
Jꢁ7.6 Hz), 8.14 (d, 2H, Jꢁ7.6 Hz).
/
/
The compound 21 from 20 [11] was achieved by the
same method as described for the preparation of 2
3.33. (2S,4R)-4-Benzoyloxy-2-[(4-
ethoxycarbonyl)thiazole-2-ylmethyl]-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (24)
1
(89.9%). H-NMR(CDCl3): d 2.42 (bs, 1H), 2.75ꢀ
/
2.99
(bs, 3H), 3.86 (bs, 1H), 4.01 (bs, 1H), 4.55 (bs, 2H), 5.09
and 5.32 (s and dd, 2H, Jꢁ11.2 Hz), 5.78 and 6.55 (bs,
2H), 7.49 (m, 4H), 7.69 (d, 1H, Jꢁ7.0 Hz), 7.94 (d, 2H,
Jꢁ7.0 Hz), 8.13 (d, 2H, Jꢁ7.0 Hz).
/
/
The compound 24 was achieved by the same method
as described for the preparation of 3. 1H-NMR
/
/
(CDCl3): d 1.40 (t, 3H, Jꢁ
2H), 3.05 (bs, 2H), 3.98ꢀ4.07 (bs, 2H), 4.16 (q, 2H, Jꢁ
7.3 Hz), 4.95 (bs, 1H), 5.15 (bs, 1H), 5.61 (bs, 2H), 7.15
(s, 1H), 7.51 (t, 3H, Jꢁ8.5 Hz), 7.68 (t, 1H, Jꢁ8.5 Hz),
7.96 (d, 2H, Jꢁ8.5 Hz), 8.14 (d, 2H, Jꢁ8.5 Hz).
/
7.3 Hz), 2.75ꢀ
/
2.81 (bs,
3.29. (2S,4R)-4-Benzoyloxy-2-[(4-
/
/
methoxycarbonylmethyl)thiazole-2-ylmethyl]-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (22)
/
/
/
/
The compound 22 was achieved by the same method
as described for the preparation of 14 (84.8%). 1H-NMR
(CDCl3): d 2.75ꢀ
3H), 3.64ꢀ4.01 (bs, 4H), 4.95 (bs, 1H), 5.15ꢀ
and s, 2H), 5.69 (bs, 1H), 7.05 (s, 1H), 7.29 (t, 2H, Jꢁ
8.1 Hz), 7.49 (d, 1H, Jꢁ8.0 Hz), 7.62 (t, 1H, Jꢁ8.0
Hz), 7.78 (m, 3H), 8.17 (d, 1H, Jꢁ7.9 Hz), 8.29 (d, 1H,
Jꢁ8.0 Hz).
/
2.85 (bs, 2H), 3.41 (bs, 2H), 3.55 (s,
3.34. (2S,4S)-2-(4-Ethoxycarbonylthiazole-2-
ylmethyl)-4-mercaptan-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (25l)
/
/5.38 (bs
/
/
/
/
Compound 25l was prepared from 24 by a similiar
method to that described for the preparation of 25a. 1H-
/
NMR (CDCl3): d 1.30 (t, 3H, Jꢁ
2.88 (bs, 1H), 3.28 (bs, 2H), 3.86 (bs, 1H), 4.04 (bs, 1H),
4.12 (q, 2H, Jꢁ7.1 Hz), 5.19ꢀ5.36 (bs, 2H), 5.49 (bs,
2H), 6.50 and 6.62 (2bs, 2H), 7.02 (s, 1H), 7.27 (d, 1H,
Jꢁ7.1 Hz), 7.69 (d, 1H, Jꢁ7.1 Hz), 8.09 (d, 1H, Jꢁ7.1
Hz), 8.19 (d, 1H, Jꢁ7.1 Hz).
/
7.1 Hz), 2.22 (bs, 1H),
3.30. (2S,4S)-2-(4-Carbamoylmethylthiazole-2-
ylmethyl)-4-mercaptan-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (25j)
/
/
/
/
/
Compound 25j was prepared from 22 by a similiar
method to that described for the preparation of 25c. 1H-
NMR (CDCl3): d 2.19 (bs, 1H), 2.80 (bs, 1H), 3.30 (bs,
/
2H), 3.65ꢀ
and s, 2H), 5.45 (bs, 1H), 5.99 (bs, 1H), 6.17 (bs, 1H),
7.02 (s, 1H), 7.48 (d, 2H, Jꢁ7.6 Hz), 8.17 (d, 2H, Jꢁ
7.6 Hz).
/
4.04 (bs, 4H), 4.91 (bs, 1H), 5.15ꢀ5.38 (bs
/
3.35. (2S,4S)-2-(4-Carbamoylthiazole-2-ylmethyl)-4-
mercaptan-1-(p-nitrobenzyloxycarbonyl)pyrroIidine
(25m)
/
/
Compound 25m was prepared from 24 by a similiar
method to that described for the preparation of 25c. 1H-
NMR (CDCl3): d 2.20 (bs, 1H), 2.89 (bs, 1H), 3.44 (bs,
3.31. (2S,4R)-4-Mesyloxy-2-[(4-
methoxycarbonylmethyl)thiazole-2-ylmethyl]-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (23)
2H), 3.88 (bs, 1H), 4.00 (bs, 1H), 4.77 (bs, 1H), 5.16ꢀ
5.28 (bs, 2H), 5.45 (bs, 1H), 7.09 (s, 1H), 7.25 (d, 1H,
Jꢁ7.1 Hz), 7.69 (d, 1H, Jꢁ7.1 Hz), 8.12 (d, 1H, Jꢁ7.1
Hz), 8.23 (d, 1H, Jꢁ7.1 Hz).
/
The compound 23 was achieved by the same method
as described for the preparation of 4. 1H-NMR
(CDCl3): d 2.15 (bs, 1H), 2.83 (bs, 1H), 3.02 (s, 3H),
/
/
/
/
3.43 (bs, 2H), 3.55 (s, 3H), 3.64ꢀ
1H), 5.15ꢀ5.35 (bs and s, 2H), 5.69 (bs, 1H), 7.02 (s,
1H), 7.49 (d, 2H, Jꢁ8.0 Hz), 8.17 (d, 2H, Jꢁ7.9 Hz).
/
4.01 (bs, 4H), 4.95 (bs,
/
3.36. (2S,4S)-2-(4-Hydroxymethylthiazole-2-
ylmethyl)-4-mercaptan-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (25n)
/
/
3.32. (2S,4S)-2-[4-(2-Hydroxyethyl)thiazole-2-
ylmethyl]-4-mercaptan-1-(p-
nitrobenzyloxycarbonyl)pyrrolidine (25k)
Compound 25n was prepared from 24 by a similiar
method to that described for the preparation of 25b. 1H-
NMR (CDCl3): d 2.22 (bs, 1H), 2.88 (bs, 1H), 3.28 (bs,
Compound 25k was prepared from 23 by a similiar
method to that described for the preparation of 25b. 1H-
2H), 3.86 (bs, 1H), 4.04ꢀ
2H), 5.49 (bs, 2H), 6.50 and 6.62 (2bs, 2H), 7.02 (s, 1H),
7.27 (d, 1H, Jꢁ7.1 Hz), 7.69 (d, 1H, Jꢁ7.1 Hz), 8.09
(d, 1H, Jꢁ7.1 Hz), 8.19 (d, 1H, Jꢁ7.1 Hz)
/
4.31 (bs, 3H), 5.19ꢀ
/
5.36 (bs,
NMR (CDCl3): d 2.11 (bs, 1H), 2.69ꢀ
/
2.89 (bs, 3H), 3.28
5.39
/
/
(bs, 2H), 3.69ꢀ4.05 (bs, 4H), 4.95 (bs, 1H), 5.17ꢀ
/
/
/
/

C.-H. Oh et al. / European Journal of Medicinal Chemistry 37 (2002) 743ꢀ
/
754
753
3.37. p-Nitrobenzyl (1R,5S,6S)-6-[(1R)-
hydroxyethyl]-3-[5-(4-ethoxycarbonyllthiazole-2-yl)-1-
(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio]-1-
methylcarbapen-2-em-3-carboxylate (27a)
HRMS (FAB): Calc. for C18H24N3O5S2: 426.1157.
Found [Mꢄ
H]ꢄ: 426.1162%.
Compound 28c: Yield: 41.2%. UV: lmax 298 nm. M.p.
115ꢀ
123 8C (dec.). 1H-NMR (D2O): d 1.08 (d, 3H, Jꢁ
7.1 Hz), 1.22 (d, 3H, Jꢁ 6.0 Hz), 2.23 (m, 1H), 2.89 (m,
1H), 3.11 (bs, 2H), 3.53 (dd, 1H, Jꢁ 6.0 Hz), 3.85 (m,
1H), 4.01 (bs, 2H), 4.55 (m, 1H), 5.15 (t, 1H, Jꢁ 8.1
Hz), 8.11 (s, 1H). IR (KBr): 3480 (OH), 3260 (NH),
1670 (CÄ HRMS (FAB): Calc. for
O) cmꢂ1
C18H23N4O5S2: 439.1110. Found [Mꢄ
H]ꢄ: 439.1104%.
Compound 28d: Yield: 37.9%. UV: lmax 298 nm. M.p.
132ꢀ
142 8C (dec.). 1H-NMR (D2O): d 1.05 (d, 3H, Jꢁ
6.7 Hz), 1.15 (d, 3H, Jꢁ 6.0 Hz), 1.96 (bs, 1H), 2.79 (m,
1H), 2.98 (bs, 1H), 3.22ꢀ3.29 (bs, 2H), 3.57 (q, 1H, Jꢁ
/
/
/
/
A solution of p-nitrobenzyl (1R,5S,6S)-3-(diphenyl-
phosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarba-
pen-2-em-3-carboxylate (26, 0.54 g, 0.91 mmol) in
CH3CN (50 mL) was cooled to 0 8C under N2. To
this solution was added diisopropylethylamine (0.13 g,
1.0 mmol) and a solution of the mercapto compound
25a (0.40 g, 0.91 mmol) in CH3CN (10 mL). After
stirring for 2 h, the mixture was diluted with EtOAc,
washed with 10% NaHCO3, brine, and dried over
anhydrous MgSO4. Evaporation in vacuo gave a
foam, which was purified by silica gel chromatography
/
/
/
.
/
/
/
/
/
/
5.9 Hz), 3.82 (m, 1H), 4.11 (m, 2H), 4.23 (s, 2H), 4.44
(bs, 1H), 7.59 (s, 1H). IR (KBr): 3540 (OH, NH2), 3270
1
to give 27a as a yellow foam solid. Yield: 79.3%. H-
(NH), 1705, 1665 (CÄ
C18H25N4O4S2: 425.1317. Found [Mꢄ
Compound 28e: Yield: 34.5%. UV: lmax 296 nm. M.p.
133ꢀ
134 8C (dec.). 1H-NMR (D2O): d 1.07 (d, 3H, Jꢁ
6.7 Hz), 1.18 (d, 3H, Jꢁ 6.0 Hz), 1.90 (m, 1H), 2.79ꢀ
2.88 (m, 1H), 3.01 (s, 3H), 3.13 (dd, 1H, Jꢁ 4.1 Hz),
3.32ꢀ3.38 (bs, 2H), 3.57 (q, 1H, Jꢁ 5.9 Hz), 3.85 (m,
1H), 4.11ꢀ4.20 (m, 2H), 4.23 (s, 2H), 4.48 (bs, 1H), 7.51
(s, 1H). IR (KBr): 3510 (OH), 3300 (NH), 1710, 1690
(CÄO), 1220 (SÄ
O) cmꢂ1. HRMS (FAB): Calc. for
C19H27N4O6S3: 503.1093. Found [Mꢄ
H]ꢄ: 503.1099%.
Compound 28f: Yield: 23.8%. UV: lmax 298 nm. M.p.
156ꢀ
160 8C (dec.). 1H-NMR (D2O): d 1.09 (d, 3H, Jꢁ
6.5 Hz), 1.16 (d, 3H, Jꢁ 6.0 Hz), 2.21 (m, 1H), 2.98 (m,
1H), 3.57ꢀ3.76 (m, 3H), 3.82 (m, 2H), 4.09ꢀ4.23 (m,
3H), 4.44 (bs, 1H), 5.10 (t, 1H, Jꢁ 6.6 Hz), 7.49 (s, 1H).
IR (KBr): 3510 (OH), 3270 (NH), 2210 (CÄN), 1710,
/
O) cmꢂ1. HRMS (FAB): Calc. for
NMR (CDCl3): d 1.25 (d, 3H, Jꢁ
(dd, 6H, Jꢁ 6.6 Hz), 1.98 (bs, 1H), 2.14 (m, 1H), 2.46
(m, 1H), 2.95 (m, 2H), 3.45 (d, 2H, Jꢁ 9.6 Hz), 4.01ꢀ
4.18 (m, 4H), 4.43 (bs, 1H), 5.11ꢀ5.55 (m, 2H), 7.09 (s,
1H), 7.23 (d, 2H, Jꢁ 7.3 Hz), 7.45 (d, 2H, Jꢁ 7.3 Hz),
8.21 (d, 4H, Jꢁ 7.3 Hz). IR (KBr): 3410 (OH), 3230
(NH), 1720, 1705, 1660 (CÄ
O) cmꢂ1
/
6.6 Hz), 1.31ꢀ
/
1.37
/
H]ꢄ: 425.1316%.
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
.
/
/
/
3.38. (1R,5S,6S)-6-[(1R)-Hydroxyethyl]-3-[5-(4-
ethoxycarbonylthiazole-2-yl)pyrrolidin-3-ylthio]-1-
methylcarbapen-2-em-3-carboxylic acid (28a)
/
/
/
/
Compound 27a (0.24 g, 0.06 mmol) and 0.1 g of Pdꢀ
/C
/
/
(10%) were dissolved in THFꢀphosphate 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
/
1680 (CÄ
/
O) cmꢂ1
.
HRMS (FAB): Calc. for
washed with water (2ꢃ/10 mL). The combined filtrate
C19H23N4O4S2: 435.1161. Found [Mꢄ
/
H]ꢄ: 435.1154%.
1
Compound 28g: Yield: 40.1%. UV: lmax 298 nm. H-
was washed with ethyl ether (2ꢃ/20 mL) and lyophilised
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
lyophilised again to give the title compound 27a as a
white powder. Yield: 47.9%. UV: lmax 298 nm. M.p.
NMR (D2O): d 1.08 (d, 3H, Jꢁ
Jꢁ 7.0 Hz), 2.16 (m, 1H), 2.93 (m, 1H), 3.23ꢀ
2H), 3.65 (m, 1H), 3.85 (s, 2H), 4.01 (bs, 1H), 4.25 (bs,
2H), 4.55 (bs, 1H), 5.01 (t, 1H, Jꢁ 8.3 Hz), 7.38 (s, 1H).
IR (KBr): 3480 (OH), 3260 (NH), 1730, 1690, 1670 (CÄ
O) cmꢂ1. HRMS (FAB): Calc. for C19H25N4O5S2:
453.1266. Found [Mꢄ
H]ꢄ: 453.1278%.
Compound 28h: Yield: 32.9%. UV: lmax 298 nm. M.p.
155ꢀ
159 8C (dec.). 1H-NMR (D2O): d 1.16 (d, 3H, Jꢁ
7.2 Hz), 1.21 (d, 3H, Jꢁ 6.4 Hz), 2.14 (m, 1H), 2.86 (m,
1H), 2.96 (t, 2H, Jꢁ 6.4 Hz), 3.21ꢀ3.39 (m, 3H), 3.59
(dd, 1H, Jꢁ 5.4 and 5.8 Hz), 3.76 (t, 2H, Jꢁ 6.4 Hz),
3.90 (bs, 1H), 4.10 (m, 1H), 4.43 (m, 1H), 4.95 (t, 1H,
Jꢁ 6.6 Hz), 7.24 (s, 1H). IR (KBr): 3500 (OH), 3320
(NH), 1710, 1690 (CÄ
O) cmꢂ1. HRMS (FAB): Calc. for
C19H26N3O5S2: 440.1314. Found [Mꢄ
H]ꢄ: 440.1315%.
Compound 28i: Yield: 29.8%. UV: lmax 298 nm. M.p.
127ꢀ
130 8C (dec.). 1H-NMR (D2O): d 1.12 (d, 3H, Jꢁ
7.2 Hz), 1.21 (d, 3H, Jꢁ 6.4 Hz), 2.24 (s, 3H), 2.46 (m,
1H), 2.66 (m, 1H), 3.11ꢀ3.39 (m, 3H), 3.59 (dd, 1H, Jꢁ
/
7.8 Hz), 1.22 (d, 3H,
/
/
3.43 (m,
/
/
145ꢀ
6.5 Hz), 1.15 (d, 3H, Jꢁ
Hz), 2.04 (bs, 1H), 2.86 (m, 1H), 3.01ꢀ
3.53 (bs, 2H), 3.70 (bs, 1H), 4.10 (m, 2H), 4.15 (q, 2H,
Jꢁ 6.1 Hz), 4.51 (bs, 1H), 7.11 (s, 1H). IR (KBr): 3470
(OH), 3230 (NH), 1710, 1690, 1660 (CÄ
O) cmꢂ1
HRMS (FAB): Calc. for C20H26N3O6S2: 468.1263.
Found [Mꢄ
H]ꢄ: 468.1272%.
Compound 28b: Yield: 35.0%. UV: lmax 298. M.p.
145ꢀ
151 8C (dec.). 1H-NMR (D2O): d 1.16 (d, 3H, Jꢁ
6.4 Hz), 1.21 (d, 3H, Jꢁ 6.4 Hz), 2.14 (m, 1H), 2.86 (m,
1H), 2.75 (m, 2H), 3.01ꢀ3.13 (bs, 2H), 3.53 (dd, 1H, Jꢁ
5.4 and 5.8 Hz), 3.97 (bs, 1H), 4.10 (m, 2H), 4.43 (m,
1H), 4.91 (t, 1H, Jꢁ 6.6 Hz), 7.11 (s, 1H). IR (KBr):
3510 (OH), 3300 (NH), 2990, 1710, 1690 (CÄ
O) cmꢂ1
/
150 8C (dec.). 1H-NMR (D2O): d 1.06 (d, 3H, Jꢁ
5.7 Hz), 1.29 (t, 3H, Jꢁ 6.1
3.13 (bs, 2H),
/
/
/
/
/
/
/
/
/
/
.
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
.
/
/

754
C.-H. Oh et al. / European Journal of Medicinal Chemistry 37 (2002) 743ꢀ754
/
5.4 and 5.8 Hz), 3.79 (bs, 1H), 3.90 (bs, 1H), 4.15 (m,
2H), 4.43 (m, 1H), 4.95 (t, 1H, Jꢁ 6.6 Hz). IR (KBr):
3500 (OH), 3320 (NH), 1710, 1680 (CÄ
O) cmꢂ1. HRMS
(FAB): Calc. for C19H26N3O5S2: 440.1314. Found [Mꢄ
H]ꢄ: 440.1319%.
Compound 28j: Yield: 31.3%. UV: lmax 298 nm. H-
NMR (D2O): d 1.09 (d, 3H, Jꢁ 7.7 Hz), 1.20 (d, 3H,
Jꢁ 7.0 Hz), 2.11 (m, 1H), 2.90 (m, 1H), 3.21ꢀ3.47 (m,
4H), 3.65 (m, 1H), 3.85 (s, 2H), 3.99 (bs, 1H), 4.21 (bs,
2H), 4.55 (bs, 1H), 5.01 (t, 1H, Jꢁ 8.3 Hz), 7.35 (s, 1H).
IR (KBr): 3500 (OH), 3320 (NH), 1710, 1690, 1665 (CÄ
O) cmꢂ1. HRMS (FAB): Calc. for C20H27N4O5S2:
467.1423. Found [Mꢄ
H]ꢄ: 467.1432%.
Compound 28k: Yield: 32.9%. UV: lmax 298 nm. H-
NMR (D2O): d 1.16 (d, 3H, Jꢁ 7.2 Hz), 1.21 (d, 3H,
Jꢁ
6.5 Hz), 3.22ꢀ
5.8 Hz), 3.71 (t, 2H, Jꢁ
1H), 4.43 (m, 1H), 4.98 (t, 1H, Jꢁ
IR (KBr): 3500 (OH), 3320 (NH), 1710, 1690 (CÄ
cmꢂ1
HRMS (FAB): Calc. for C20H28N3O5S2:
454.1470. Found [Mꢄ
H]ꢄ: 454.1463%.
Compound 28l: Yield: 29.5%. UV: lmax 298 nm. H-
NMR (D2O): d 1.07 (d, 3H, Jꢁ 6.9 Hz), 1.15 (d, 3H,
Jꢁ 5.9 Hz), 1.30 (t, 3H, Jꢁ 6.1 Hz), 2.04 (bs, 1H), 2.86
(m, 1H), 3.01ꢀ3.13 (bs, 2H), 3.53ꢀ3.77 (bs, 4H), 3.70
(bs, 1H), 4.10 (m, 2H), 4.11 (q, 2H, Jꢁ 6.1 Hz), 4.51 (bs,
1H), 7.11 (s, 1H). IR (KBr): 3470 (OH), 3230 (NH),
1710, 1690, 1660 (CÄ
O) cmꢂ1. HRMS (FAB): Calc. for
C21H28N3O6S2: 482.1420. Found [Mꢄ
H]ꢄ: 482.1433%.
Compound 28m: Yield: 23.0%. UV: lmax 298 nm. 1H-
NMR (D2O): d 1.08 (d, 3H, Jꢁ 7.1 Hz), 1.20 (d, 3H,
Jꢁ 6.2 Hz), 2.20 (m, 1H), 2.89 (m, 1H), 3.11 (bs, 2H),
3.38ꢀ3.53 (m, 3H), 3.82 (m, 1H), 4.02 (bs, 2H), 4.50 (m,
1H), 5.11 (t, 1H, Jꢁ 8.1 Hz), 7.47 (s, 1H). IR (KBr):
3510 (OH), 3320 (NH), 1710, 1690, 1660 (CÄ
O) cmꢂ1
HRMS (FAB): Calc. for C19H25N4O5S2: 453.1266.
Found [Mꢄ
H]ꢄ: 453.1269%.
Compound 28n: Yield: 30.9%. UV: lmax 298 nm. H-
NMR (D2O): d 1.16 (d, 3H, Jꢁ 6.4 Hz), 1.21 (d, 3H,
Jꢁ 6.4 Hz), 2.14 (m, 1H), 2.86 (m, 1H), 2.75 (m, 2H),
3.01ꢀ3.13 (bs, 2H), 3.31ꢀ3.55 (m, 3H), 3.93 (bs, 1H),
4.11 (m, 2H), 4.45 (m, 1H), 4.99 (t, 1H, Jꢁ 6.6 Hz), 7.17
(s, 1H). IR (KBr): 3500 (OH), 3320 (NH), 1710, 1690
/
/
1
/
/
/
/
1
/
/
/
/
/
/
(CÄ
/
O) cmꢂ1. HRMS (FAB): Calc. for C19H26N3O5S2:
440.1314. Found [Mꢄ
/
H]ꢄ: 440.1320%.
/
/
References
/
1
[1] For
a
recent review on the current state of carbapenem
/
antibiotics, see: S. Coultion, E. Hunt, in: G.P. Ellis, D.K.
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/
6.4 Hz), 2.10 (m, 1H), 2.85 (m, 1H), 2.99 (t, 2H, Jꢁ
/
/
3.51 (m, 5H), 3.59 (dd, 1H, Jꢁ
/
5.4 and
Elsevier, 1996, pp. 99ꢀ
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145.
/
6.5 Hz), 3.90 (bs, 1H), 4.11 (m,
6.9 Hz), 7.25 (s, 1H).
O)
/
/
/
/
.
[3] (a) L.C. Waddel, R.W. Ratcliffe, S.P. Szumiloski, K.J. Wildonger,
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320.
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128.
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.