Optical resolution of 5-oxo-1-phenyl-pyrazolidine-3-carboxylic acid as a new organocatalyst for organic reactions

Article abstract of DOI:10.1002/jccs.200800091

Optical resolution of racemic 5-oxo-1-phenyl-pyrazolidine-3-carboxylic acid 2 with L-amino acid methyl ester via the diastereomers formation was investigated. Treatment of racemic 5-oxo-1-phenylpyrazolidine-3-carboxylic acid 2 with L-valine methyl ester g

Full text of DOI:10.1002/jccs.200800091

626
Journal of the Chinese Chemical Society, 2008, 55, 626-631
Optical Resolution of 5-Oxo-1-phenyl-pyrazolidine-3-carboxylic Acid as a
New Organocatalyst for Organic Reactions
Zheng-Hao Tzeng (
Pang-Min Liu (
), Shuen-Wen Yang (
) and Kwun-Min Chen* (
),
)
Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan 116, R.O.C.
Optical resolution of racemic 5-oxo-1-phenyl-pyrazolidine-3-carboxylic acid 2 with L-amino acid
methyl ester via the diastereomers formation was investigated. Treatment of racemic 5-oxo-1-phenyl-
pyrazolidine-3-carboxylic acid 2 with L-valine methyl ester gave diastereomers with a total yield of 86%.
The diastereomeric dipeptides can be easily separated by flash column chromatography. Acidic cleavage
of the derived diastereomers gave both the optically pure (+)-(R)- and (-)-(S)-5-oxo-1-phenyl-pyrazoli-
dine-3-carboxylic acid ((+)-(R)-2 and (-)-(S)-2) with a total yield of 94% and 95%, respectively.
Keywords: Optical resolution; Organocatalyst; 5-Oxo-1-phenyl-pyrazolidine-3-carboxylic acid;
L-Amino acid.
INTRODUCTION
The rapid development of metal free small molecules
amino acid methyl ester to provide diastereomers with high
overall material yield. The diastereomeric compounds
were then separated by flash column chromatography and
further hydrolysis to give both enantiomers with high opti-
cal purity as measured by optical rotation.
for various stereoselective catalysis requires an increasing
demand of novel structural organocatalysts.1 The catalyti-
cal enantioselective transformations for the preparation of
useful intermediates with structural diversity is an ongoing
endeavor in organic synthesis. Recently, asymmetric syn-
thesis by using optically pure organocatalysts has attracted
much attention for the construction of various C-C bonds,
such as aldol,2 Mannich,3 Michael addition,4 Diels-Alder
Reactions,5 etc. Small organic molecules such as L-proline
1 and its derivatives have emerged as a viable strategy for
stereochemical reactions since 2000.6 Many reaction types
have been studied and high to excellent stereoselectivities
were achieved. The mechanistic explanation was proposed
that involves the stabilization of a transition state confor-
mation with hydrogen bonding.7 Optical resolution of
racemic materials is a conventional approach to prepare
enantiomeric pure chiral compounds.8 In this communica-
tion, we describe an efficient optical resolution of racemic
5-oxo-1-phenyl-pyrazolidine-3-carboxylic acid 2 with L-
RESULTS AND DISCUSSION
The starting racemic 5-oxo-1-phenyl-pyrazolidine-3-
carboxylic acid 2 can be easily prepared by the reported
procedure.9 Treatment of maleic acid with phenylhydra-
zine under refluxing conditions in H2O for 8 h provided the
desired product with 72% yield (Scheme I). The chemical
structure of 2 was determined by 1H-, 13C-NMR and HRMS
analyses and further confirmed by single crystal X-ray
analysis of its methyl ester derivative 3 (conc. H2SO4,
MeOH, reflux 3 h, 65% yield).
Scheme I
O
O
OR
PhNHNH2
OH
OH
NH
O
H2O, 8 h, 72 %
N
Ph
O
2 : R = H
3 : R = Me
An efficient resolution of diastereomeric mixtures
has been documented on the difference in solubility of the

Optical Resolution of a New Organocatalyst
J. Chin. Chem. Soc., Vol. 55, No. 3, 2008 627
pair salts.10 Initially, we studied the possibility to co-crys-
tallize one of the diastereomeric salts of 5-oxo-1-phenyl-
pyrazolidine-3-carboxylic acid 2 using different resolving
agents (e.g. (R,R)- and (S,S)-1,2-diamino-cyclohexane,
and Quinine). Many attempts that failed led us to seek the
covalent bond formation of diastereomers and subsequent
separation. We first screened various L-amino acid methyl
esters for the reason that the dipeptide–like compounds can
serve as useful organocatalysts when the methyl ester func-
tional group was hydrolyzed to the corresponding carbox-
ylic acid.11 Toward this end, racemic 5-oxo-1-phenyl-pyra-
zolidine-3-carboxylic acid 2 was treated with di-tert-butyl
dicarbonate as its N-Boc protected compound. Amide bond
formation of the Boc-protected 2 was then treated with var-
ious L-amino acid methyl esters in the presence of coupling
reagents (N,N-dicyclohexylcarbodiimide (DCC), 3-ethyl-
1-(3-dimethyl-amino-propyl)-carbodiimide·HCl (EDC)
and 1-hydroxybenzotriazole (HOBt)) under the standard
conditions. The use of L-phenylalanine methyl ester af-
forded the desired diastereomeric pair of products with
moderate yield (49%) when DCC (1.1 equiv) and HOBt
(1.1 equiv) were used (entry 1). We then fine-tuned the re-
action conditions by varying the amount of the coupling re-
agents and studying the temperature effect of the amide
bond formation. Acomparable result was obtained when an
excess of DCC (4.0 equiv) was used while the material
yield decreased in the absence of HOBt (entries 2 and 3).
On the other hand, suitable amounts of DCC (1.2 equiv)
and HOBt (0.2 equiv) used at ambient temperature afforded
the desired product with a total yield of 65% (entry 4). A
slight improvement in chemical yield was observed when
the reaction was carried out at 0 oC (entry 5). Finally, an ex-
cellent yield was obtained when racemic compound 2 was
treated with EDC (1.2 equiv) and HOBt (0.2 equiv) at 0 oC
(entry 6). The reaction can be scaled up for gram quantities
(30 g) to give the desired product in 79% total yield.
Table 1. Optical resolution of racemic 5-oxo-1-phenyl-pyrazoli-
dine-3-carboxylic acid 2 by L-phenylalanine methyl
estera
Ph
1. Boc2O, Et3N, MeCN
O
2. L-Phenylalanine methyl ester,
DCC, HOBt, Et3N, CH2Cl2
N
H
CO2Me
(+)-2
-
NBoc
O
N
Ph
(R, S)-4
(S, S)-4
DCC / HOBt
T
t
Yield (%)b
(anti + syn)
Entry
(equiv)
(oC)
(h)
1
2
3
4
5
6
1.1 / 1.1
4.0 / 0.2
4.0 / 0
1.2 / 0.2
1.2 / 0.2
1.2 / 0.2
rt
rt
rt
16
4
24
6
8
10
24 + 25
25 + 26
< 10
32 + 33
33 + 36
45 + 49c
rt
0 oC to rt
0 oC to rt
a Boc-Protected 2 (200 mg, 0.65 mmol), DCC, HOBt in dichloro-
methane were allowed to stir at ambient temperature for 1 h
followed by the addition of L-phenylalanine methyl ester and Et3N
(1.2 equiv).
b Isolated yield.
c Boc-Protected 2, L-phenylalanine methyl ester, HOBt, Et3N (1.2
equiv) in dichloromethane at 0 oC followed by the addition of EDC.
assignment (Fig. 1). Five amino acid derivatives were stud-
ied and, except for L-histidine methyl ester, the other four
The proximity in polarity of the corresponding dias-
tereomers [(Rf = 0.21 and 0.17 (hexanes/EtOAc = 3/1), re-
spectively] cause the separation (flash column chromatog-
raphy) to be a challenging task. In addition, many attempts
to crystallize both or either of the diastereomers for abso-
lute stereochemistry determination failed.
We then turned our attention to the synthesis of other
pairs of diastereomers by using other L-amino acid methyl
esters under the optimum reaction conditions with the hope
of crystallization of any diastereomer for stereochemistry
Fig. 1. Chemical structures of the diastereomers of
compounds 5-9 and the stereoview of the
Chem3D structure of (R,S)-5 (regenerated from
X-ray crystal coordinates).

628 J. Chin. Chem. Soc., Vol. 55, No. 3, 2008
Tzeng et al.
desired adducts were obtained with high chemical yields
(84~90%) in a roughly 1:1 ratio. Among the five diastereo-
meric pairs of products, only L-phenylalanine and L-valine
methyl ester derivatives can be easily separated by flash
column chromatography (hexanes/EtOAc). Fortunately,
the easy crystallization of L-valine methyl ester derived
(R)-5-oxo-1-phenyl-pyrazolidine-3-carboxylic acid ((R,S)-
5) from CH2Cl2/hexanes allowed the assignment of abso-
lute stereochemistry of both the diastereomers.
(400 MHz for 1H, and 100 MHz for 13C). Chemical shifts
are reported in d ppm referenced to an internal TMS stan-
dard for 1H NMR and chloroform-d (d 77.0) for 13C NMR.
Optical rotations were measured on a JASCO P-1010
polarimeter. EI mass spectra were recorded on a Finnigan
TSQ-700 instrument at an ionizing energy of 70 eV and
HRMS spectra were recorded on a JEOL SX-102A. Rou-
tine monitoring of reactions was performed using silica gel,
glass-backed TLC plates (Merck Kieselgel 60 F254) and
visualized by UV light (254 nm). Solvents were evaporated
to dryness under reduced pressure using a rotary evapora-
tor and the residue was purified by flash column chroma-
tography on silica gel (230-400 mesh) with the indicated
eluents. Air and/or moisture sensitive reactions were per-
formed under inert atmosphere conditions.
With the optical pure L-valine methyl ester derived
(R)- and (S)-5-oxo-1-phenyl-pyrazolidine-3-carboxylic
acid in hand, we then removed the resolving agent and Boc
protecting group under acidic conditions. Treatment of
(R,S)-5 with 1 N HCl in refluxing H2O for 2 h afforded the
enantiomeric pure (+)-(R)-2 ([a] 2D0 +50.0 (c 0.5, MeOH))
with 94% yield (Scheme II). The antipode product (-)-(S)-2
([a] 2D0 -48.6 (c 0.5, MeOH)) was obtained in 95% yield
when (S,S)-5 was used under the same reaction conditions.
Preparation of racemic 2
A mixture of maleic acid (5.0 g, 43.07 mmol) and
phenylhydrazine (6.4 mL, 64.60 mmol) in water (50 mL)
was stirred under refluxing conditions for 8 h. The mixture
was cooled down to ambient temperature; at that time the
precipitate which appeared was filtered off. The aqueous
filtrate was extracted with CH2Cl2 (20 mL) and the layers
were separated. The aqueous layer was acidified to pH = 0
~ 2 with 1 N HCl, and then extracted with EtOAc (30 mL ´
5). The combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated in vacuo. The
crude product was washed with CHCl3 (20 mL ´ 5) to af-
ford racemic 2 (6.39 g, 72%) as a white solid.
The acidic hydrolysis and deprotection of
Scheme II
diastereomer (R,S)-5 and (S,S)-5
Me
O
Me
CO2Me
O
OH
N
1 N HCl
H
H2O, reflux, 2 h
NH
O
NBoc
N
N
O
Ph
Ph
(+)-(R)-2 : (94%)
(-)-(S)-2 : (95%)
(R, S)-5
(S, S)-5
Preparation of racemic methyl 5-oxo-1-phenylpyra-
zolidine-3-carboxylate 3
To a solution of the racemic compound 2 (0.5 g, 2.43
mmol) was added 5% H2SO4 in MeOH (20.0 mL) dropwise
and the mixture was brought to refluxing conditions for 3 h.
The mixture was diluted with H2O (20 mL) and extracted
with EtOAc (40 mL ´ 2). The combined organic layers
were washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by
flash column chromatography on silica gel using hexanes/
EtOAc (2/1) as eluent to give white solid of 3 (0.35 g,
65%). IR (CHCl3) n 3648, 2958, 1741, 1700, 1597, 1498,
1235 cm-1. 1H NMR (400 MHz, CDCl3) d 7.80 (d, 2H, J =
8.04 Hz), 7.35 (t, 2H, J = 8.04 Hz), 7.13 (t, 1H, J = 7.36
Hz), 5.28 (d, 1H, J = 9.68 Hz), 4.36 (dd, 1H, J = 18.40, 9.68
Hz), 3.82 (s, 3H), 2.97 (m, 2H). 13C NMR (100 MHz,
CDCl3) d 171.27, 168.40, 138.27, 128.80, 124.74, 118.54,
55.32, 52.96, 37.92. HRMS m/z 220.0849 (calcd for
In summary, we have developed an efficient method
for the first optical resolution of (+)-(R)- and (-)-(S)-5-oxo-
1-phenyl-pyrazolidine-3-carboxylic acid 2. High overall
yield (58% yield) of the resolved products were obtained
and the process can be carried out with gram quantities.
The optical pure enantiomer of (+)-(R)-2 and (-)-(S)-2 pos-
sesses a unique pyrazolidine structure and can be used as an
organocatalyst in asymmetric reactions. The studies of
organocatalysis using (+)-(R)-2 and (-)-(S)-2 for various
organic reactions are actively underway in our group.
EXPERIMENTAL
General Methods
All reagents were used as purchased from commer-
cial suppliers without further purification. NMR spectra
were recorded on a Bruker Avance 400 NMR spectrometer

Optical Resolution of a New Organocatalyst
J. Chin. Chem. Soc., Vol. 55, No. 3, 2008 629
C11H12N2O3: 220.0848). Anal. Calcd for C11H12N2O3: C,
59.99; H, 5.49; N, 12.72. Found: C, 60.03; H, 5.58; N,
12.71. Crystal data for 3 at 200 K: C11H12N2O3, M 220.23,
Triclinic, P-1, a = 6.7266(2) Å, b = 8.2764(3) Å, c =
10.3861(4) Å, V = 522.56(3) Å3, Z = 2, l = 0.71073 Å, Dc =
1.400 Mg/m3, m = 0.104 mm-1, 6960 reflections, 146 pa-
rameters, R = 0.0763, Rw = 0.1953 for all data.
1720, 1689, 1597, 1496, 1154 cm-1. 1H NMR (400 MHz,
CDCl3) d 7.4-7.2 (m, 5H), 7.11 (t, 1H, J = 7.12 Hz), 7.09-
6.95 (m, 3H), 6.88 (d, 2H, J = 6.68 Hz), 4.97 (dd, 1H, J =
8.52, 2.92 Hz), 4.84 (q, 1H, J = 6.24 Hz), 3.77 (s, 3H), 3.25
(dd, 1H, J = 13.92, 5.12 Hz), 3.18-3.05 (m, 2H), 3.00 (dd,
1H, J = 13.92, 6.36 Hz), 1.25 (s, 9H). 13C NMR (100 MHz,
CDCl3) d 171.55, 168.61, 167.63, 156.00, 138.45, 135.08,
128.88, 128.66, 128.53, 127.02, 125.09, 119.24, 84.64,
59.14, 53.65, 52.56, 37.44, 34.36, 27.67. HRMS m/z
467.2059 (calcd for C25H29N3O6: 467.2056). Anal. Calcd
for C25H29N3O6: C, 64.23; H, 6.25; N, 8.99. Found: C,
64.12; H, 6.20; N, 8.90.
General procedure of the optical resolution for the
preparation of a diastereomeric pair of products
To a solution of racemic 2 (135.0 mg, 0.66 mmol) in
MeCN (15 mL) was added Boc2O (0.17 mL, 0.79 mmol)
and Et3N (0.10 mL, 0.72 mmol) dropwise at ambient tem-
perature. The mixture was allowed to stir for 2 h and was
diluted with H2O (20 mL) and extracted with EtOAc (40
mL ´ 2). The combined organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated in vacuo
to give the Boc-protected crude product.
(R)-tert-butyl-5-((S)-1-methoxy-3-methyl-1-oxobu-
tan-2-ylcarbamoyl)-3-oxo-2-phenylpyrazolidine-1-car-
boxylate (R,S)-5: mp. 122.8-124.2 oC. IR (CHCl3) n 3426,
2967, 1752, 1724, 1637, 1436, 1228 cm-1. 1H NMR (400
MHz, CDCl3) d 7.56 (d, 2H, J = 8.40 Hz), 7.38 (dd, 2H, J =
8.40, 7.64 Hz), 7.30 (d, 1H, J = 4.24 Hz), 7.18 (t, 1H, J =
7.64 Hz), 5.05 (dd, 1H, J = 10.00, 1.88 Hz), 4.58 (dd, 1H, J
= 8.96, 4.24 Hz), 3.67 (s, 3H), 3.30 (dd, 1H, J = 17.36, 1.80
Hz), 3.15 (dd, 1H, J = 17.36, 10.00 Hz), 2.30-2.20 (m, 1H),
1.35 (s, 9H), 1.00 (d, 3H, J = 6.88 Hz), 0.97 (d, 3H, J = 6.92
Hz). 13C NMR (100 MHz, CDCl3) d 171.67, 168.64,
167.86, 156.21, 138.37, 128.68, 125.54, 120.24, 84.67,
59.04, 57.38, 52.18, 33.40, 31.45, 27.70, 18.88, 17.63.
HRMS m/z 419.2065 (calcd for C21H29N3O6: 419.2056).
Anal. Calcd for C21H29N3O6: C, 60.13; H, 6.97; N, 10.02.
Found: C, 59.81; H, 6.95; N, 9.90. Crystal data for (R,S)-5
at 200 K: C21H29N3O6, M 419.47, Monoclinic, P21, a =
6.3290(2) Å, b = 14.4830(5) Å, c = 12.3790(5) Å, V =
1100.95(7) Å3, Z = 2, l = 0.71073 Å, Dc = 1.265 Mg/m3, m
= 0.093 mm-1, 6696 reflections, 272 parameters, R =
0.0660, Rw = 0.1486 for all data.
To a solution of the crude Boc-protected product (200
mg, 0.65 mmol) in dry CH2Cl2 (4 mL) was added L-phenyl-
alanine methyl ester · HCl (169.1 mg, 0.78 mmol) and
HOBt (17.7 mg, 0.13 mmol) at 0 oC. After the addition of
Et3N (0.12 mL, 0.85 mmol) and EDC (150.3 mg, 0.78
mmol), the mixture was allowed to warm up to ambient
temperature for 10 h. The mixture was diluted with CH2Cl2
(10 mL) and H2O was added (10 mL). The layers were sep-
arated and the organic layer was washed with brine, dried
over MgSO4, filtered, and concentrated in vacuo. The
crude products were purified by flash column chromatog-
raphy on silica gel using hexanes/EtOAc (6/1) as eluent to
afford the corresponding pairs of diastereomer 4.
(R)-tert-butyl-5-((S)-1-methoxy-1-oxo-3-phenylpro-
pan-2-ylcarbamoyl)-3-oxo-2-phenylpyrazolidine-1-car-
boxylate (R,S)-4: mp. 127.5-128.5 oC. IR (CHCl3) n 3414,
1719, 1654, 1497, 1153 cm-1. 1H NMR (400 MHz, CDCl3)
d 7.35-7.21 (m, 8H), 7.16-7.09 (m, 3H), 5.00 (dd, 1H, J =
11.52, 2.24 Hz), 4.92 (dt, 1H, J = 8.56, 5.40 Hz), 3.55 (s,
3H), 3.24-3.08 (m, 4H), 1.29 (s, 9H). 13C NMR (100 MHz,
CDCl3) d 170.98, 168.32, 167.60, 156.03, 138.20, 135.37,
129.34, 128.66, 128.55, 127.27, 125.21, 119.67, 84.57,
59.22, 52.95, 52.22, 37.75, 33.82, 27.63. HRMS m/z
467.2059 (calcd for C25H29N3O6: 467.2056). Anal. Calcd
for C25H29N3O6: C, 64.23; H, 6.25; N, 8.99. Found: C,
64.12; H, 6.20; N, 8.90.
(S)-tert-butyl-5-((S)-1-methoxy-3-methyl-1-oxobu-
tan-2-ylcarbamoyl)-3-oxo-2-phenylpyrazolidine-1-car-
boxylate (S,S)-5: mp. 104.7-106.5 oC. IR (CHCl3) n 3320,
2975, 1730, 1701, 1682, 1597, 1500, 1153 cm-1. 1H NMR
(400 MHz, CDCl3) d 7.58 (d, 2H, J = 7.80 Hz), 7.37 (t, 2H,
J = 7.80 Hz), 7.22 (d, 1H, J = 8.60 Hz), 7.16 (t, 1H, J = 7.44
Hz), 5.06 (dd, 1H, J = 6.92, 4.56 Hz), 4.57 (dd, 1H, J =
8.60, 4.64 Hz), 3.77 (s, 3H), 3.19 (s, 1H), 3.18 (d, 1H, J =
2.44 Hz), 2.18-2.07 (m, 1H), 1.35 (s, 9H), 0.79 (d, 3H, J =
6.84 Hz), 0.74 (d, 3H, J = 6.92 Hz). 13C NMR (100 MHz,
CDCl3) d 171.89, 168.69, 168.24, 156.08, 138.69, 128.82,
125.24, 118.79, 84.86, 59.63, 57.36, 52.30, 34.64, 31.21,
27.75, 18.67, 17.42. HRMS m/z 419.2065 (calcd for
(S)-tert-butyl-5-((S)-1-methoxy-1-oxo-3-phenylpro-
pan-2-ylcarbamoyl)-3-oxo-2-phenylpyrazolidine-1-car-
boxylate (S,S)-4: mp. 117.5-118.2 oC. IR (CHCl3) n 3406,

630 J. Chin. Chem. Soc., Vol. 55, No. 3, 2008
Tzeng et al.
C21H29N3O6: 419.2056).
84.77, 84.74, 67.80, 67.50, 59.55, 59.10, 57.50, 57.32,
52.63, 52.51, 34.49, 33.79, 27.66, 19.92, 19.82. HRMS m/z
421.1847 (calcd for C20H27N3O7: 421.1849).
(R)- and (S)-tert-butyl-5-((S)-3-(1H-indol-3-yl)-1-
methoxy-1-oxopropan-2-ylcarbamoyl)-3-oxo-2-phenyl-
pyrazolidine-1-carboxylate 6: An inseperable mixture of
Preparation of (+)-(R)- and (-)-(S)-5-oxo-1-phenyl-
pyrazolidine-3-carboxylic acid 2
1
diastereomers. Selected peaks of the diastereomers: H
NMR (400 MHz, CDCl3) d 8.35 (s, 1H), 7.64 (s, 1H), 7.58
(d, 1H, J = 7.80 Hz), 7.38 (t, 3H, J = 7.44 Hz), 7.32 (d, 1H, J
= 8.60 Hz), 7.25-6.90 (m, 15H), 6.54 (d, 1H, J = 2.20 Hz),
5.10-4.80 (m, 4H), 3.75 (s, 3H), 3.48-3.03 (m, 11H), 1.80
(s, 1H), 1.25 (s, 18H). 13C NMR (100 MHz, CDCl3) d
171.99, 171.51, 168.65, 168.46, 167.88, 167.84, 156.20,
155.95, 138.32, 138.18, 136.23, 136.04, 128.67, 128.53,
127.54, 127.01, 125.23, 125.12, 123.26, 123.21, 122.39,
121.99, 120.01, 119.46, 119.43, 119.34, 118.56, 118.06,
111.38, 109.53, 108.69, 84.79, 84.60, 59.57, 59.52, 53.15,
52.98, 52.72, 52.29, 34.76, 34.26, 27.71, 27.67, 27.48,
27.24. HRMS m/z 506.2159 (calcd for C27H30N4O6:
506.2165).
To a solution of diastereomer (R,S)-5 (0.5 g, 1.07
mmol) was added 1 N HCl (10 mL) and the reaction was
brought to reflux for 2 h. The mixture was extracted with
EtOAc (20 mL ´ 3). The combined organic layers were
washed with brine, dried over MgSO4, filtered, and concen-
trated in vacuo. The crude products were washed with
CHCl3 (10 mL ´ 2), afforded (+)-(R)-2 as a white solid
(207.4 mg, 94%; [a] 2D0 +50.0 (c 0.5, MeOH)). Diaster-
eomer (S,S)-5 (0.5 g, 1.07 mmol) was used under the same
conditions to afforded the white solid of (-)-(S)-2 (209.6
mg, 95%; [a] 2D0 -48.6 (c 0.5, MeOH)). mp. 217.2-218.5 oC.
1H NMR (400 MHz, DMSO-d6) d 7.80 (d, 2H, J = 8.08 Hz),
7.36 (t, 2H, J = 8.08 Hz), 7.10 (t, 1H, J = 7.34 Hz), 4.27 (dd,
1H, J = 8.44, 5.96 Hz), 3.00 (dd, 1H, J = 16.44, 8.44 Hz),
2.79 (dd, 1H, J = 16.44, 5.96 Hz). 13C NMR (100 MHz,
DMSO-d6) d 172.81, 170.54, 139.48, 128.96, 124.10,
118.40, 55.37, 37.78. HRMS m/z 206.0695 (calcd for
C10H10N2O3: 206.0691).
(R)- and (S)-tert-butyl 5-((S)-1,3-di(methoxycarbon-
yl)-propylcarbamoyl)-3-oxo-2-phenylpyrazolidine-1-car-
boxylate 7: An inseperable mixture of diastereomers. Se-
1
lected peaks of the diastereomers: H NMR (400 MHz,
CDCl3) d 7.63-7.45 (m, 6H), 7.42-7.33 (m, 4H), 7.16 (td,
2H, J = 7.40, 3.44 Hz), 5.07-5.01 (m, 2H), 4.70-4.58 (m,
2H), 3.79 (s, 3H), 3.72 (s, 3H), 3.68 (s, 3H), 3.60 (s, 3H),
3.30-3.09 (m, 4H), 2.53-1.92 (m, 8H), 1.35 (s, 9H), 1.30 (s,
9H). 13C NMR (100 MHz, CDCl3) d 173.17, 172.93,
171.74, 171.55, 168.91, 168.15, 167.84, 156.32, 156.11,
138.68, 138.48, 128.79, 128.66, 125.44, 125.28, 120.06,
119.13, 84.77, 84.74, 59.39, 59.15, 52.69, 52.60, 51.98,
51.95, 51.91, 51.79, 34.28, 33.70, 29.95, 29.46, 27.73,
27.72, 27.22, 26.93. HRMS m/z 463.1961 (calcd for
C22H29N3O8: 463.1955).
ACKNOWLEDGMENTS
This work was supported by the National Science
Council of the Republic of China (NSC 95-2113-M-003-
001) and National Taiwan Normal University (96TOP001).
Received July 11, 2007.
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