Synthesis and transformations of novel L -phenylalanine derived pyrazolidin-3-ones

Article abstract of DOI:10.1002/chir.22166

A simple and straightforward four-step synthesis of novel diastereomeric L-phenylalanine-derived pyrazolidin-3-ones is described. The absolute configuration of the novel C(5) stereogenic centre has been unambiguously determined by single crystal X-ray analysis and via chemical interconversions. A series of novel thiourea derived pyrazolidinones have been prepared and tested as potential organocatalysts. N(1) un-substituted pyrazolidinones can be used for the construction of a novel type of bicyclic heterocycles and other selective derivatizations. 2013 Wiley Periodicals, Inc.

Full text of DOI:10.1002/chir.22166

CHIRALITY 25:541–555 (2013)
Synthesis and Transformations of Novel L-Phenylalanine Derived
Pyrazolidin-3-ones
1
1
1,2
UROŠ GROŠELJ, AMALIJA GOLOBIC, JURIJ SVETE, AND BRANKO STANOVNIK1,2
ꢀ
*
1
ꢀ
ꢀ
University of Ljubljana, Faculty of Chemistry and Chemical Technology, Askerceva cesta 5, P.O. Box 537, SI-1000 Ljubljana, Slovenia
2EN-FIST Centre of Excellence, Dunajska 156, SI-1000 Ljubljana, Slovenia
ABSTRACT
A simple and straightforward four-step synthesis of novel diastereomeric L-phenylalanine-
derived pyrazolidin-3-ones is described. The absolute configuration of the novel C(5)
stereogenic centre has been unambiguously determined by single crystal X-ray analysis
and via chemical interconversions. A series of novel thiourea derived pyrazolidinones have
been prepared and tested as potential organocatalysts. N(1) un-substituted pyrazolidinones
can be used for the construction of a novel type of bicyclic heterocycles and other selective
derivatizations. Chirality 25:541–555, 2013.
© 2013 Wiley Periodicals, Inc.
KEY WORDS: b-keto ester; hydrazine cyclization; pyrazolidin-3-ones; (thio)ureas; tetrahydro-
1H-imidazo[1,5-b]pyrazole-2,6-dione
INTRODUCTION
has been reported.34 N(1)- and C(5)-Disubstituted pirazolidin-3-
ones have been prepared using Diels-Alder cycloaddition
strategy for the kinetic resolution of chiral pyrazolidinones.35
Similarly, kinetic resolutions of azomethine imines via copper-
catalyzed [3 + 2] cycloadditions gave pirazolidinones as single
enantiomers.36 Rhodium-catalyzed asymmetric arylation of
azomethine imines yielded chiral 1-(diarylmethyl)pyrazolidin-3-
ones.37 Direct electrophilic amination of homoenolates
catalyzed by N-heterocyclic carbenes furnished trisubstituted
pyrazolidinones38 while diastereoselective 1,3-dipolar cycload-
dition of hydrazones with a-oxo-ketenes gave spiropyrazolidin-
3-ones.39 Highly enantioselective Brønsted acid catalyzed
cycloaddition between alkenes and N-benzoylhydrazones lead
to various optically active pyrazolidine derivatives.40 Nonracemic
pyrazolidinones have been prepared from enantiomerically
pure 2,3-disubstituted oxirane carboxylic acids.41 Ring
switching methodology was used to prepare optically active
diastereoizomeric pyrazolidin-3-ones.42–44
To the best of our knowledge, we could find no chiral
nonracemic C(5)-substituted pyrazolidin-3-one diastereoisomers
of type A prepared from chiral pool amino acid derivatives
(Scheme 1). A literature search for compounds of type A re-
vealed pyrazolidin-3-ones with alanine43 and serine42,44
side chain residue (R) and a non-proteinogenic side chain
(R = CO2R)45. This prompted us to investigate the
preparation of pyrazolidin-3-ones of type A starting from
N-Cbz-protected L-phenylalanine as a model amino acid
via the corresponding keto ester, and cyclization with
hydrazines in the final step. Additional functionalizations
Pyrazolidin-3-one derivatives, both mono and bicyclic,
remain attractive targets due to their diverse applicabilities
and bioactivities as well as the challenges associated with
their enantio- and/or diastereoselective synthesis. Thus,
pyrazolidinone derivatives have been employed as dyes in
food and other industries.1–3 Their bioactivities range from
analgesic and antipyretic in phenazone,4–6 anti-inflammatory
in phenylbutazone,4–6 anorectic in BW357U,7 to inhibitory
activities of cyclooxygenase and lipoxygenase in BW755C
and phenidone, respectively.8,9 Bicyclic pyrazolidinones are
used, among others, as drugs to relieve Alzheimer’s disease10
and as antibacterial agents.11–15 Camphor derived pyrazolidin-
3-one has been successfully employed as chiral auxiliary16–21
while achiral pyrazolidinone templates have been used in
enantioselective Diels-Alder cycloadditions in conjunction
with chiral Lewis acids.22–24 Several studies have demonstrated
the potential of pyrazolidin-3-ones as a new scaffold in
organocatalysis. Ogilvie and co-workers successfully applied
camphor derived pyrazolidin-3-one as a covalent organocatalyst
in cycloaddition reactions,25–28 while Smith et al. studied
structural effects in pyrazolidin-3-one mediated organocatalytic
Diels-Alder reactions.29 Research into acyclic- and cyclic 5- and
6-membered hidrazides conducted by Tomkinson et al. may
come useful in the design of novel pyrazolidin-3-one catalysts
and their 6-membered counterparts.30–32
For further development of pyrazolidin-3-one derivatives in
asymmetric catalysis, and other applications, an easy access
to nonracemic pyrazolidin-3-one templates with diverse
substituents at C(4)- and/or C(5)-positions, with the desired
spatial orientation, are needed. Nonracemic pyrazolidin-3-
ones have been accessed via simple diastereoizomeric
derivatization of racemic pyrazolidinones followed by
separation/deprotection.29 Highly enantioselective addition
of monosubstituted hydrazines to a,b-unsaturated imides
using catalytic amounts of chiral Lewis acids has been
reported giving N(1) and C(5)-substituted pyrazolidin-3-ones.33
Asymmetric organocatalyzed synthesis of N(1), N(2) protected
5-alkyl substituted pirazolidin-3-ones based on the aza-Michael/
hemiaminalization reaction of a,b-unsaturated aldehydes and
hydrazides under iminium activation followed by PCC oxidation
© 2013 Wiley Periodicals, Inc.
Additional Supporting Information may be found in the online version of this
article.
Contract grant sponsor: Slovenian Research Agency (financial support)
Contract grant numbers: P1-0179 and J1-0972
Contract grant sponsor: Ministry of Science and Technology, Republic of
Slovenia (financial contribution for the purchase of Kappa CCD Nonius
diffractometer)
Contract grant numbers: Packet X-2000 and PS-511-102
ꢀ
ꢀ
*Correspondence to: Uros Groselj, University of Ljubljana, Faculty of
ꢀ
ꢀ
Chemistry and Chemical Technology, Askerceva cesta 5, P.O. Box 537,
1000 Ljubljana, Slovenia. E-mail: uros.groselj@fkkt.uni-lj.si
Received for publication 02 January 2013; Accepted 01 February 2013
DOI: 10.1002/chir.22166
Published online 13 June 2013 in Wiley Online Library
(wileyonlinelibrary.com).

ꢀ
542
GROsELJ ET AL.
Catalytic hydrogenation–General Procedure 1 (GP1). To a solution
or suspension of amine(s) (1 equivalent) in MeOH (V) under
argon was added Pd–C (10% on C), the reaction vessel was
flushed with H2, and the reaction mixture was hydrogenated in
a Paar hydrogenator (P = 4 Bar) at room temperature for 1 h.
The reaction mixture was filtered through a plug of Celite
and washed with MeOH (100 mL). Volatile components were
evaporated in vacuo, and the residue was dried on high
vacuum and used in the following transformations without
further purification.
Scheme 1. Synthesis of a-amino acid derived pyrazolidin-3-ones.
of pyrazolidinones were carried out in order to establish
the configuration of the newly created stereogenic centre
as well as to prepare some potential new organocatalysts.
The results of this preliminary study are reported herein.
Preparation of (thio)urea derivatives–General Procedure 2 (GP2).
To a solution or suspension of amine(s) (1 equivalent) in
anhydrous solvent (V) under argon at 0 ꢀC was added iso
(thio)cyanate (1 equivalent) and the resulting mixture was
stirred for 30minutes at 0 ꢀC and 24 h at room temperature.
Volatile components were evaporated in vacuo and the residue
was purified/separated by column chromatography (CC) or
MPLC. Fractions containing the separated product(s) were
combined and volatile components evaporated in vacuo.
EXPERIMENTAL
Materials and Methods
All reactions were performed under Argon in dried glassware using
anhydrous solvents, except when using aqueous reagents. Solvents for
extractions and chromatography were of technical grade and were
distilled prior to use. Extracts were dried over technical grade Na2SO4.
Melting points were determined on a Kofler micro hot stage and on
SRS OptiMelt MPA100-Automated Melting Point System (Stanford
Research Systems, Sunnyvale, CA, USA). The NMR spectra were
obtained on a Bruker UltraShield 500 plus (Bruker, Billerica, MA, USA)
at 500 MHz for 1H and 126 MHz for 13C nucleus, using DMSO-d6 and
CDCl3 with TMS as the internal standard, as solvents. Mass spectra were
recorded on an Agilent 6224 Accurate Mass TOF LC/MS (Agilent
Technologies, Santa Clara, CA, USA), IR spectra on a Perkin-Elmer
Spectrum BX FTIR spectrophotometer (PerkinElmer, Waltham, MA, USA).
Microanalyses were performed on a Perkin-Elmer CHN Analyzer 2400 II
(S)-Methyl 4-(((benzyloxy)carbonyl)amino)-3-oxo-5-phenylpentanoate46
(2). Carbonyl-1,1’-diimidazole (CDI) (7.89 g, 43.8 mmol) was
added at room temperature to a stirred solution of (S)-2-
(((benzyloxy)carbonyl)amino)-3-phenylpropanoic acid (1) (11.92 g,
39.8mmol) in anhydrous THF (80 mL) under argon. The
resulting mixture was stirred for 2 h at room temperature
and used in the next step without any purification. Mean-
while, a solution of lithium enolate of MeOAc was prepared
in the following way. LDA (90 mL, c = 2 M (in THF/heptane/
ethylbenzene), 180 mmol) was added to anhydrous THF
(80 mL) at –61 ꢀC under argon, followed by dropwise addition
of a solution of anhydrous MeOAc (14.3 mL, 180 mmol) in
anhydrous THF (20 mL) under argon at –61 ꢀC over a period
of 15 minutes. After stirring of enolate at –61ꢀC for 1.5 h, the
above prepared solution of imidazolide of 1 was added
dropwise over the period of 30minutes. The resulting mixture
was stirred for 2 h and then quenched at –61ꢀC with NaHSO4
(1 M in H2O) and extracted with EtOAc (3Â 200 mL). The
combined organic phase was washed with NaHCO3 (aq. sat.,
2 Â 50mL) and NaCl (aq. sat., 50 mL), dried over anhydrous
Na2SO4, and volatile components evaporated in vacuo. The
residue was purified by column chromatography (EtOAc/
petroleum ether = 1:4). Fractions containing the product 2
were combined and volatile components evaporated in
vacuo. Yield: 6.08 g (43%) of yellowish solid; mp 79–80 ꢀC
(PerkinElmer). Catalytic hydrogenation was performed on
a Parr
Pressure Reaction Hydrogenation Apparatus (Moline, IL, USA). Column
chromatography (CC) was performed on silica gel (Silica gel 60, particle size:
0.035-0.070 mm, (Sigma-Aldrich, St. Louis, MO, USA). Medium-pressure
liquid chromatography (MPLC) was performed with Büchi Flash
Chromatography System (BUCHI Labortechnik AG, Flawil, Switzerland)
(Büchi Fraction Collector C-660, Büchi Pump Module C-605, Büchi Control
Unit C-620) on silica gel (LiChrosphere Si 60 (12 mm) and/or LiChroprep Si
60 (15-25 mm) (Merck, KGaA, Darmstadt, Germany); column dimensions
(wet filled): 22 Â 460 mm, 36 Â 460 mm and 40 Â 460 mm; backpressure:
10–20 Bar; detection: UV 254 nm. Low temperatures were maintained using
Julabo FT902 immersion cooler (JULABO GmbH, Seelbach, Germany).
All chemicals were of reagent grade and used as supplied, unless
stated otherwise. Z-L-phenylalanine (1), carbonyl-1,1’-diimidazole
(CDI), lithium diisopropylamide (LDA), THF (anhydrous), MeOAc,
NaBH4, MsCl, hydrazine, methylhydrazine, trans-cinnamaldehyde, 1-
methylindole, dimethyl malonate, trans-b-nitrostyrene, 10% palladium
on charcoal, DMF (anhydrous), Boc2O, MeI, tBuOK, HCHO,
NaCNBH3, trifluoroacetic acid (TFA), 3,5-bis(trifluoromethyl)phenyl
isothiocyanate (13), 1-isothiocyanatonaphthalene (19), phenyl isocya-
nate (21), 4-methylphenyl isocyanate (22), and 4-bromophenyl isocy-
anate (25) were purchased from Sigma-Aldrich.
(lit46: mp = 78-80 ꢀC). [a]rD.t.
= +8.8 (c = 0.16, CHCl3).
(C20H21NO5 requires: C, 67.59; H, 5.96; N, 3.94; found C,
67.48; H, 5.80; N, 3.97); EI-HRMS: m/z = 356.1493 (MH+);
C20H22NO5 requires: m/z = 356.1492 (MH+); nmax 3337,
3031, 2952, 1708, 1604, 1513, 1497, 1454, 1437, 1401,
1318, 1241, 1148, 1075, 1042, 1027, 844, 738, 697 cm-1.
Source of chirality: Z-L-phenylalanine (1), product number 359807,
[a]rD.t. = +5 (c = 5 in acetic acid), ee not specified, mp 85-87 ꢀC.
1H-NMR (500 MHz, DMSO-d6):
d 2.70 (dd, J = 13.9;
10.6 Hz, Ha-C(5)); 3.10 (dd, J = 13.9; 4.3 Hz, Hb-C(5)); 3.62
(s, CO2Me); 3.71 (s, H2C(2)); 4.35 (ddd, J = 10.6; 8.2;
4.3 Hz, H-C(4)); 4.97 (s, CH2); 7.19–7.37 (m, 10H of Ph);
7.81 (d, J = 8.3 Hz, NH). 13C-NMR (126 MHz, DMSO-d6): d
34.7, 45.8, 51.9, 61.4, 65.5, 126.4, 127.5, 127.8, 128.2,
128.3, 129.2, 136.9, 137.7, 156.0, 167.4, 202.4.
Syntheses
The structures of novel compounds 3, 4, 5-7/5’-7’, 8, 9-12/9’-12’,
14, 15, 16/16’, 18/18’, 20/20’, 23, 24, and 26/26’ were deter-
mined by spectroscopic methods (1H-NMR, 13C-NMR, 2D-NMR, IR,
HRMS) and by elemental analyses for C, H, and N. Compounds 4, 5/
5’, 6/6’, 8, 9’, 10/10’, 12/12’, 14, 15, 16/16’, 20/20’, and 24 were
not obtained in analytically pure form. Their identities were confirmed by
13C-NMR and HRMS. Mixtures of epimers 5/5’, 11/11’, and 12/12’
were characterized as mixtures of epimers. Single compounds or mix-
tures of epimers 8/8’, 15/15’, 17, and 17’ were used in the following
transformation without any or partial characterization.
(3R,4S)-Methyl
phenylpentanoate (3) and (3S,4S)-methyl 4-(((benzyloxy)car-
bonyl)amino)-3-hydroxy-5-phenylpentanoate47 (3’). To
4-(((benzyloxy)carbonyl)amino)-3-hydroxy-5-
a
solution of b-keto ester 2 (2.79 g, 7.85 mmol) in MeOH (30 mL)
Chirality DOI 10.1002/chir

SYNTHESIS OF PHENYLALANINE DERIVED PYRAZOLIDINONES
543
cooled to –5ꢀC was added NaBH4 (305 mg, 7.85 mmol) and the
resulting mixture was stirred at –5 ꢀC for 1 h and then quenched
at –5ꢀC by the addition of H2O (150 mL) followed by the addition
of HCl (10 mL, 1 M in H2O). The resulting suspension was
stirred at 0 ꢀC for 30 minutes, filtered, the collected product
washed with H2O (200 mL), and dried on high vacuum. Yield:
2.33 g (83%) of white solid (3:3’= 1:0.16). The epimers 3/3’ were
separated by MPLC (EtOAC/petroleum ether = 1:2). Fractions
containing the separated epimers 3/3’ were combined,
respectively, and volatile components evaporated in vacuo.
Alternatively, re-crystallization of the epimer mixture 3/3’
from EtOAc/n-heptane gave pure 3.
55.0, 65.1, 79.7, 126.3, 127.3, 127.6, 128.2, 128.3, 129.0,
137.1, 138.0, 155.9, 170.0.
Benzyl ((S)-1-((R)-5-oxopyrazolidin-3-yl)-2-phenylethyl)carbamate
(5) and benzyl ((S)-1-((S)-5-oxopyrazolidin-3-yl)-2-phenylethyl)
carbamate (5’). To a solution of mesylate 4 (3.18 g, 7.3 mmol)
in CH2Cl2 (50 mL) was added hydrazine monohydrate
(2.5 mL, 51.4 mmol) and the resulting mixture was stirred at
room temperature for 24 h. Volatile components were evapo-
rated in vacuo and the residue was purified by flash CC
(EtOAc/MeOH = 10:1). Fractions containing the products
were combined and volatile components evaporated in vacuo
to give the crude mixture of products 5/5’ in a ratio of 1:0.62,
respectively, and in 100% conversion. The residue was re-
purified by CC (EtOAc/MeOH= 15:1). Fractions containing
the products 5/5’ were combined and volatile components
evaporated in vacuo. Yield: 1.41 g (57%; 5:5’ = 1:0.43) of
dirty yellow oil. [a]Dr.t. = –26.3 (c = 0.28, CHCl3). EI-HRMS:
m/z = 340.1653 (MH+); C19H22N3O3 requires: m/z = 340.1656
(MH+); nmax 3358, 3280, 3248, 3064, 3032, 2932, 1693, 1682,
1658, 1530, 1496, 1453, 1317, 1246, 1143, 1131, 1082, 1050,
1028, 975, 935, 899, 770, 736, 696, 649 cm-1. 1H-NMR
(500MHz, DMSO-d6) for 5: d 2.18 (dd, J = 16.3; 6.0 Hz, Ha-C
(4)); 2.37 (dd, J = 16.2; 7.9 Hz, Hb-C(4)); 2.56 (dd, J = 13.8;
10.3 Hz, Ha-C(7)); 3.00 (dd, J = 13.7; 3.2 Hz, Hb-C(7));
3.39–3.46 (m, H-C(5)); 3.66–3.75 (m, H-C(6)); 4.90 (d,
J = 12.9 Hz, Ha of CH2); 4.97 (d, J = 12.9, Hb of CH2); 5.45
(d, J = 7.5 Hz, H-N(1)); 7.14–7.37 (m, 10H of Ph, NH);
9.08 (s, H-N(2)). 1H-NMR (500 MHz, DMSO-d6) for 5’: d
2.24 (dd, J = 16.4; 7.4 Hz, Ha-C(4)); 2.61 (dd, J = 13.6;
10.4 Hz, Ha-C(7)); 2.83 (dd, J = 13.7; 4.3 Hz, Hb-C(7));
3.54–3.62 (m, H-C(5)); 3.77–3.84 (m, H-C(6)); 4.91
(d, J = 12.8 Hz, Ha of CH2); 4.97 (d, J = 12.8Hz, Hb of CH2);
5.28 (d, J = 7.4 Hz, H-N(1)); 9.01 (s, H-N(2)). 13C-NMR
(126MHz, CDCl3) for 5 and 5’: d 34.1, 34.5, 36.1, 37.0, 54.2,
54.8, 59.4, 60.2, 64.9, 65.0, 125.9, 126.1, 127.2, 127.3, 127.6,
128.0, 128.1, 128.3, 129.1, 129.2, 137.2, 137.3, 138.8, 138.9,
156.0, 156.1, 175.01, 175.03.
Compound 3’: Elutes first. Yield: 224 mg (8%) of white solid;
mp 95-98 ꢀC (lit47: mp = 99.5ꢀC). EI-HRMS: m/z = 358.1646
1
(MH+); C20H24NO5 requires: m/z = 358.1649 (MH+). H-NMR
(500 MHz, DMSO-d6): d 2.29 (dd, J = 15.4, 9.6 Hz, Ha-C(2));
2.48 (d, J = 15.4; 3.4 Hz, Hb-C(2)); 2.58 (dd, J = 13.7; 10.1 Hz,
Ha-C(5)); 2.86 (dd, J = 13.7; 4.5 Hz, Hb-C(5)); 3.58 (s, CO2Me);
3.69–3.77 (m, H-C(4)); 3.93–4.00 (m, H-C(3)); 4.93 (d, J=12.9Hz,
Ha of CH2); 4.97 (d, J=12.9Hz, Hb of CH2); 5.13 (d, J=5.7Hz,
OH); 7.13 (d, J= 9.2 Hz, NH); 7.17–7.35 (m, 10H of Ph).
Compound 3: Elutes second. Yield: 1.68g (60%) of yellowish
solid; mp 131-133 ꢀC. [a]Dr.t. = –4.3 (c= 0.07, CHCl3). (C20H23NO5
requires: C, 67.21; H, 6.49; N, 3.92. found C, 67.05; H,
6.25; N, 3.94); EI-HRMS: m/z = 358.1648 (MH+); C20H24NO5
requires: m/z= 358.1649 (MH+); nmax 3323, 3031, 2948, 1728,
1695, 1604, 1534, 1496, 1438, 1373, 1358, 1302, 1260, 1233,
1192, 1164, 1141, 1101, 1085, 1049, 1015, 981, 911, 883, 840,
1
775, 761, 738, 694, 609 cm-1. H-NMR (500 MHz, DMSO-d6):
d 2.37 (dd, J = 15.0; 9.5 Hz, Ha-C(2)); 2.55–2.64 (m, Hb-C
(2), Ha-C(5)); 3.08 (dd, J = 13.9; 3.1 Hz, Hb-C(5)); 3.58–3.69
(m, CO2Me, H-C(4)); 3.85–3.93 (m, H-C(3)); 4.92 (d, J = 12.9 Hz,
Ha of CH2); 5.00 (d, J= 12.9, Hb of CH2); 5.27 (d, J=6.8Hz, OH);
7.18–7.41 (m, 10H of Ph, NH). 13C-NMR (126 MHz, DMSO-d6):
d 35.9, 39.4, 51.3, 57.3, 64.8, 70.3, 125.8, 127.2, 127.6,
128.0, 128.3, 129.1, 137.4, 139.4, 155.9, 172.0.
(3R,4S)-Methyl 4-(((benzyloxy)carbonyl)amino)-3-((methylsulfonyl)
oxy)-5-phenylpentanoate (4). To a solution of b-hydroxy ester 3
(762 mg, 2.13 mmol) in pyridine (5 mL, 61.8 mmol) cooled to –
5ꢀC was added MsCl (214 mL, 2.77 mmol) and the resulting
mixture was stirred at –5 ꢀC for 1 h and further 2 h at room
temperature. The reaction mixture was poured into cooled
(0 ꢀC) PhMe (150 mL) and washed thoroughly with HCl
(70 mL, 1 M in H2O). The aqueous phase was discarded and
the organic phase was washed with NaCl (aq. sat, 2 Â 50 mL).
The organic phase was dried over anhydrous Na2SO4, filtered,
and volatile components evaporated in vacuo to give crude 4
used in the following transformations without further purifica-
tions. Yield: 653 mg (70%) of white solid; mp 117–125 ꢀC. [a]Dr.t.
= –38.3 (c = 0.08, CHCl3). (C21H25NO7S requires: C, 57.92; H,
5.79; N, 3.22; found C, 58.86; H, 5.77; N, 3.32); EI-HRMS: m/
z= 436.1435 (MH+); C21H26NO7S requires: m/z = 436.1424
(MH+); nmax 3294, 3057, 1739, 1681, 1544, 1495, 1455, 1439,
1399, 1384, 1346, 1320, 1271, 1246, 1223, 1206, 1172, 1141,
1088, 1038, 1027, 1001, 985, 968, 920, 892, 822, 799, 778, 752,
705, 671, 613 cm-1. 1H-NMR (500 MHz, DMSO-d6): d 2.58
(dd, J = 13.8; 11.3 Hz, Ha-C(5)); 2.75 (dd, J = 16.1; 8.5 Hz, Ha-C
(2)); 2.88–2.96 (m, Hb-C(2), Hb-C(5)); 3.17 (s, OSO2Me); 3.63
(s, CO2Me); 4.06–4.14 (m, H-C(4)); 4.91 (d, J = 12.8 Hz, Ha of
CH2); 4.97 (d, J = 12.8 Hz, Hb of CH2); 5.03 (dt, J = 8.5;
4.2 Hz, H-C(3)); 7.14–7.35 (m, 10H of Ph); 7.52 (d, J= 9.1 Hz, NH).
13C-NMR (126 MHz, DMSO-d6): d 34.9, 36.0, 38.1, 51.8,
Benzyl ((S)-1-((S)-2-methyl-5-oxopyrazolidin-3-yl)-2-phenylethyl)
carbamate (6’), benzyl ((S)-1-((R)-2-methyl-5-oxopyrazolidin-3-
yl)-2-phenylethyl)carbamate (6), benzyl ((S)-1-((R)-1-methyl-5-
oxopyrazolidin-3-yl)-2-phenylethyl)carbamate (7), and benzyl ((S)-1-
((S)-1-methyl-5-oxopyrazolidin-3-yl)-2-phenylethyl)-carbamate (7’).
To a solution of mesylate 4 (4.25 g, 9.75 mmol) in CH2Cl2
(60 mL) was added methylhydrazine (4.21 mL, 80 mmol) and
the resulting mixture was stirred at room temperature for 24 h.
Volatile components were evaporated in vacuo and the residue
was purified by flash CC (EtOAc/MeOH = 15:1). Fractions
containing all the products were combined and volatile compo-
nents evaporated in vacuo to give the crude mixture of products
6/6’/7/7’ in a ratio of 1:0.74:0.73:0.38, respectively, and in 100%
conversion. The residue was separated by MPLC (EtOAc/
MeOH = 20:1) to give separately a mixture of 6/6’ in a ratio of
1:0.74, pure 7, and a mixture of 7/7’ in a ratio of 1:0.74,
respectively. Fractions containing the separated compounds/
mixtures were combined and volatile components evaporated
in vacuo, respectively.
Compound 7: Elutes second. Yield: 360 mg (10%) of white
solid; mp 146-148 ꢀC. [a]Dr.t.
= –38.6 (c = 0.13, CHCl3).
(C20H23N3O3 requires: C, 67.97; H, 6.56; N, 11.89. found C,
67.84; H, 6.47; N, 11.89); EI-HRMS: m/z = 354.1812 (MH+);
C20H24N3O3 requires: m/z = 354.1812 (MH+); nmax 3339,
3208, 3032, 2940, 1689, 1667, 1538, 1494, 1454, 1412, 1398,
Chirality DOI 10.1002/chir

ꢀ
GROsELJ ET AL.
544
1320, 1255, 1221, 1204, 1131, 1085, 1053, 1008, 968, 936, 899,
880, 802, 776, 739, 697, 658 cm-1. 1H-NMR (500 MHz, DMSO-
d6): d 2.27 (dd, J = 16.3; 6.1 Hz, Ha-C(4)); 2.46 (dd, J = 16.3;
8.2 Hz, Hb-C(4)); 2.55 (dd, J = 13.7; 10.3 Hz, Ha-C(7)); 2.85
(s, Me-N(2)); 2.95 (dd, J = 13.7; 3.4 Hz, Hb-C(7)); 3.31–
3.41 (m, H-C(5)); 3.62–3.72 (m, H-C(6)); 4.90 (d, J = 12.9,
Ha of CH2); 4.96 (d, J = 12.9 Hz, 1 Hb of CH2); 5.81 (d,
J = 8.1 Hz, H-N(1)); 7.14–7.38 (m, 10H of Ph, NH). 13C-
NMR (126 MHz, CDCl3): d 31.3, 34.0, 37.3, 54.0, 57.0,
67.1, 127.0, 128.1, 128.4, 128.7, 128.8, 129.3, 136.3,
137.0, 156.6, 171.0.
1H-NMR (500 MHz, DMSO-d6): d 1.38 (br s, NH2); 2.31 (dd,
J = 16.2; 8.2 Hz, Ha-C(4)); 2.43 (dd, J = 13.2; 8.5 Hz, Ha-C(7));
2.50 (dd, J = 16.0; 8.4 Hz, Hb-C(4)); 2.71 (dd, J = 13.2; 5.0 Hz,
Hb-C(7)); 2.81–2.87 (m, Me-N(2), H-C(6)); 3.19–3.26 (m, H-C
(5)); 5.63 (d, J = 8.8 Hz, H-N(1)); 7.14–7.25 (m, 3H of Ph);
7.25–7.32 (m, 2H of Ph). 13C-NMR (126 MHz, DMSO-d6): d
30.5, 32.9, 40.7, 53.9, 57.9, 125.9, 128.2, 129.2, 139.5, 170.8.
(R)-5-((S)-1-Amino-2-phenylethyl)-2-methylpyrazolidin-3-one (8) and
(S)-5-((S)-1-amino-2-phenylethyl)-2-methylpyrazolidin-3-one
(8’).
General Procedure 1 (GP1): Prepared from a mixture of epimers
7/7’ (353 mg, 1 mmol, 7:7’ =1:0.74), Pd–C (80mg), V= 40 mL.
Thoroughly dried crude mixture of products 8/8’ was used in
the following transformations (see the preparation of 9 and 9’).
Yield: full conversion (8:8’= 1:0.74); colorless oil. 1H-NMR
(500 MHz, DMSO-d6) for 8’: d 5.74 (br s, H-N(1). 13C-NMR
(126 MHz, DMSO-d6) for 8’: d 30.5, 32.9, 40.4, 54.9, 57.0, 126.0,
128.2, 129.3, 139.5, 170.6.
Compound 7’ in a mixture of 7/7’: Elutes third. Yield:
1
846 mg (24%, 7:7’ = 1:0.74) of white solid. H-NMR (500 MHz,
DMSO-d6): d 2.76 (dd, J = 13.7; 4.1 Hz, Ha-C(7)); 2.85 (s, Me-N
(2)); 3.46–3.54 (m, H-C(5)); 3.73–3.80 (m, H-C(6)); 5.75
(d, J = 8.1 Hz, H-N(1)). 13C-NMR (126 MHz, DMSO-d6): d
30.5, 30.6, 34.3, 34.5, 35.9, 36.9, 54.5, 55.1, 55.9, 56.9,
64.95, 64.96, 126.0, 126.1, 127.2, 127.59, 127.62, 128.08,
128.12, 128.29, 128.31, 129.1, 129.2, 137.29, 137.30,
138.81, 138.85, 156.1, 156.2, 170.3, 170.5.
(3aR,4S)-4-Benzyl-1-methyltetrahydro-1H-imidazo[1,5-b]pyrazole-
2,6-dione (9). To a solution of crude diamine 8 (85 mg,
0.388 mmol) in anhydrous DMF (10 mL) under argon was
added CDI (84 mg, 0.465 mmol) and the resulting mixture
was stirred at room temperature for 6 h. Volatile components
were evaporated in vacuo and the residue was purified by
CC (EtOAc). Fractions containing the product 9 were com-
bined and volatile components evaporated in vacuo. Yield:
80 mg (84%) of white solid; mp 194–195 ꢀC. [a]Dr.t. = +7.5
(c = 0.08, CHCl3). (C13H15N3O2 requires: C, 63.66; H, 6.16;
N, 17.13. found C, 63.43; H, 6.32; N, 16.94); EI-HRMS: m/
z = 246.1239 (MH+); C13H16N3O2 requires: m/z = 246.1237
(MH+); nmax 3217, 3142, 2991, 2959, 2913, 2847, 1732, 1675,
1495, 1477, 1456, 1435, 1415, 1373, 1349, 1327, 1300, 1279,
1251, 1170, 1153, 1118, 1089, 1069, 1018, 962, 895, 858, 828,
805, 763, 724, 699, 628, 605 cm-1. 1H-NMR (500 MHz,
DMSO-d6): d 2.03 (dd, J = 16.1; 7.1 Hz, Ha-C(4)); 2.77 (dd,
J = 14.0; 8.1 Hz, Ha-C(7)), 2.92 (dd, J = 14.0; 6.2 Hz, Hb-C
(7)); 3.01 (dd, J = 16.1; 11.4 Hz, Hb-C(4)); 3.10 (s, Me-N(2));
4.12–4.18 (m, H-C(6)); 4.18–4.24 (m, H-C(5)); 7.20–7.34 (m,
5H of Ph); 7.93 (s, NH). 13C-NMR (126 MHz, DMSO-d6): d
30.4, 32.4, 36.3, 51.4, 60.3, 126.6, 128.5, 128.9, 137.0, 163.7,
170.2.
The mixture of epimers 6/6’ was separated by MPLC
(CHCl3/MeOH = 60:1). Fractions containing the separated
compounds were combined and volatile components evapo-
rated in vacuo, respectively.
Compound 6’: Elutes first. Yield: 642 mg (18%) of white solid;
mp 68–69 ꢀC. [a]Dr.t. = –89.5 (c= 0.32, CHCl3). (C20H23N3O3
requires: C, 67.97; H, 6.56; N, 11.89. found C, 67.10; H, 6.62;
N, 11.66); EI-HRMS: m/z = 354.1809 (MH+); C20H24N3O3
requires: m/z= 354.1812 (MH+); nmax 3267, 3176, 3063, 3029,
2955, 2932, 2855, 1701, 1668, 1604, 1533, 1496, 1454, 1397,
1336, 1243, 1127, 1082, 1060, 1026, 954, 927, 740, 695 cm-
1
.
1H-NMR (500 MHz, DMSO-d6): d 2.22 (dd, J = 17.1;
4.4 Hz, Ha-C(4)); 2.52 (s, Me-N(1)); 2.59 (dd, J = 13.4;
11.1 Hz, Ha-C(7)); 2.80 (dd, J = 17.1; 9.4 Hz, Hb-C(4)); 2.85
(dd, J = 13.7; 3.3 , Hb-C(7)); 3.11 (dt, J = 9.5; 4.8 Hz, H-C
(5)); 3.71–3.78 (m, H-C(6)); 4.89 (d, J = 13.0 Hz, Ha of CH2);
4.95 (d, J = 12.9 Hz, Hb of CH2); 7.14–7.34 (m, 10H of Ph, NH);
9.32 (s, H-N(2)). 13C-NMR (126MHz, DMSO-d6): d 31.2, 35.3,
47.8, 55.4, 64.9, 66.2, 126.0, 127.2, 127.6, 128.1, 128.3, 129.1,
137.3, 138.9, 156.0, 172.00.
Compound 6: Elutes second. Yield: 869 mg (25%) of
white solid; mp 48-51 ꢀC. [a]Dr.t. = –1.0 (c = 0.18, CHCl3).
(C20H23N3O3 requires: C, 67.97; H, 6.56; N, 11.89. found C,
67.49; H, 6.83; N, 11.59); EI-HRMS: m/z = 354.1812 (MH+);
C20H24N3O3 requires: m/z = 354.1812 (MH+); nmax 3254,
3061, 3030, 2956, 2925, 2854, 1681, 1604, 1532, 1496, 1454,
1408, 1338, 1247, 1128, 1082, 1050, 1026, 930, 737, 695 cm-1.
1H-NMR (500 MHz, DMSO-d6): d 2.13 (dd, J = 16.9; 4.5 Hz,
Ha-C(4)); 2.51 (s, Me-N(1)); 2.56 (dd, J = 13.7; 10.8 Hz, Ha-C
(7)); 2.73 (dd, J = 16.9; 8.6 Hz, Hb-C(4)); 2.92–3.02 (m, Hb-C
(7), H-C(5)); 3.61–3.70 (m, H-C(6)); 4.89 (d, J = 12.9 Hz, Ha
of CH2); 4.97 (d, J = 12.9 Hz, Hb of CH2); 7.14–7.36 (m, 10H of
Ph, NH); 9.37 (s, H-N(2)). 13C-NMR (126 MHz, DMSO-d6): d
31.1, 36.8, 47.1, 53.8, 64.8, 67.7, 126.0, 127.1, 127.6, 128.1,
128.3, 129.0, 137.3, 139.1, 156.1, 172.13.
(3aR,4S)-4-Benzyl-1-methyltetrahydro-1H-imidazo[1,5-b]pyrazole-
2,6-dione (9) and (3aS,4S)-4-benzyl-1-methyltetrahydro-1H-imidazo
[1,5-b]pyrazole-2,6-dione (9’). To a solution of crude epimere
mixture 8/8’ (166 mg, 0.757 mmol; 8:8’ = 1:0.75) in anhydrous
DMF (10 mL) under argon was added CDI (164 mg, 0.908 mmol)
and the resulting mixture was stirred at room temperature for
6 h. Volatile components were evaporated in vacuo and the res-
idue was purified by flash CC (EtOAc). Fractions containing
both products were combined and volatile components evapo-
rated in vacuo. The products were separated by MPLC
(EtOAc/petroleum ether = 2:1). Fractions containing the sepa-
rated products were combined and volatile components evapo-
rated in vacuo to give 9 and 9’, respectively.
Compound 9: Elutes first. Yield: 92 mg (49%) of white solid.
For properties see synthesis of 9.
(R)-5-((S)-1-Amino-2-phenylethyl)-2-methylpyrazolidin-3-one (8).
General Procedure 1 (GP1): Prepared from 7 (335 mg,
0.95 mmol), Pd–C (70 mg), V = 40 mL. Thoroughly dried crude
product 8 was used in the following transformations (see the
preparation of 9 and 14). Yield: full conversion; colorless oil.
[a]rD.t. = +0.6 (c= 0.7, MeOH). EI-HRMS: m/z = 220.1446
(MH+); C12H18N3O requires: m/z = 220.1444 (MH+); nmax cm-1.
Chirality DOI 10.1002/chir
Compound 9’: Elutes second. Yield: 30 mg (16%) of white
semisolid. [a]Dr.t. = –147.7 (c = 0.22, CHCl3). (C13H15N3O2
requires: C, 63.66; H, 6.16; N, 17.13. found C, 63.75; H, 6.53;
N, 15.57); EI-HRMS: m/z = 246.123 (MH+); C13H16N3O2
requires: m/z = 246.1237 (MH+); nmax 3255, 3029, 2924, 1731,
1681, 1603, 1494, 1413, 1379, 1299, 1247, 1139, 1084, 1062,

SYNTHESIS OF PHENYLALANINE DERIVED PYRAZOLIDINONES
545
1011, 918, 892, 863, 798, 761, 720, 699, 611 cm-1. 1H-NMR
(500 MHz, DMSO-d6): d 2.32 (dd, J = 16.4, 7.8 Hz, Ha-C(4));
2.68 (dd, J = 16.3; 10.9 Hz, Hb-C(4)); 2.81 (d, J = 6.7 Hz, H2-C
(7)); 3.09 (s, Me-N(2)); 3.80 (t, J = 6.7 Hz, H-C(6)); 4.09
(dd, J = 10.7; 8.0 Hz, H-C(5)); 7.21–7.27 (m, 3H of Ph); 7.28–7.34
(m, 2H of Ph); 7.99 (s, NH). 13C-NMR (126 MHz,
DMSO-d6): d 32.3, 35.1, 40.9, 54.7, 60.0, 126.6, 128.4,
129.3, 137.0, 164.0, 169.8.
in vacuo, the residue was suspended in CH2Cl2 (150 mL),
and washed with NaHCO3 (aq. sat., 10 mL), and NaCl
(aq. sat., 10 mL). The organic phase was dried over anhy-
drous Na2SO4, filtered, and volatile components evaporated
in vacuo. The residue was purified by flash CC (EtOAc).
Fractions containing the crude product 10 were combined
and volatile components evaporated in vacuo. Yield: 43 mg
(41%) of colorless oil.
Benzyl ((S)-1-((R)-1,2-dimethyl-5-oxopyrazolidin-3-yl)-2-phenylethyl)
carbamate (10). To a solution of 6 (480 mg, 1.36 mmol) in
anhydrous DMF (10 mL) under argon was added tBuOK
(153 mg, 1.36 mmol) followed by addition of MeI (85 mL,
0.833 mmol) and the resulting mixture was stirred at room
temperature for 2 h. Volatile components were evaporated
in vacuo and the residue was purified by CC (EtOAc). Frac-
tions containing the product 10 were combined and volatile
components evaporated in vacuo. Yield: 458 mg (91%) of
colorless oil. [a]rD.t. = –6.0 (c = 0.15, CHCl3). EI-HRMS:
m/z = 368.1967 (MH+); C21H26N3O3 requires: m/z = 368.1969
(MH+); nmax 3293, 3062, 3030, 2928, 2857, 1666, 1534, 1496,
1454, 1418, 1394, 1339, 1315, 1247, 1185, 1136, 1083, 1044,
(R)-tert-Butyl 5-((S)-1-(((benzyloxy)carbonyl)amino)-2-phenylethyl)-
3-oxopyrazolidine-1-carboxylate (11) and (S)-tert-butyl 5-((S)-1-
(((benzyloxy)carbonyl)amino)-2-phenylethyl)-3-oxopyrazolidine-1-
carboxylate (11’). To a suspension of epimeres 5/5’ (340mg,
1 mmol, 5:5’= 1:0.43) in anhydrous CH2Cl2 (25 mL) were added
Et3N (140 mL, 1 mmol) and Boc2O (218mg, 1mmol) and the
resulting mixture was stirred at room temperature for 2 h.
Volatile components were evaporated in vacuo and the residue
was purified by CC (EtOAc/petroleum ether = 1:1). Fractions
containing the products were combined and volatile components
evaporated in vacuo to give the mixture of products 11/11’ in a
ratio of 1:0.5, respectively. Yield: 240 mg (54%; 11:11’ =1:0.5) of
white solid; mp 63-71 ꢀC. [a]Dr.t. = +9.3 (c = 0.08, CHCl3).
(C24H29N3O5 requires: C, 65.59; H, 6.65; N, 9.56. found C,
65.32; H, 6.33; N, 9.50). nmax 3306, 3064, 3030, 2978, 2934, 1687,
1527, 1496, 1454, 1367, 1327, 1242, 1157, 1121, 1083, 1047,
1028, 855, 739, 697 cm-1. 1H-NMR (500 MHz, DMSO-d6) for 11:
d 1.43 (s, tBu); 2.38 (d, J = 17.3 Hz, Ha-C(4)); 2.62 (dd, J= 13.6;
10.5 Hz, Ha-C(7)); 2.78 (dd, J= 14.1; 4.1 Hz, Hb-C(7)); 2.88
(dd, J = 17.1; 10.0 Hz, Hb-C(4)); 3.86–3.97 (m, H-C(6));
4.25–4.33 (m, H-C(5)); 4.87 (d, J = 12.8 Hz, Ha of CH2);
4.98 (d, J = 12.9 Hz, Hb of CH2); 7.13–7.35 (m, 10H of
Ph); 7.44 (d, J = 9.4 Hz, NH); 10.49 (s, H-N(2)). 1H-NMR
(500 MHz, DMSO-d6) for 11’: d 1.46 (s, tBu); 2.95 (dd,
J = 17.3; 10.2 Hz, Hb-C(4)); 4.43–4.48 (m, H-C(5)); 4.86
(d, J = 12.9 Hz, Ha of CH2); 4.95 (d, J = 13.2 Hz, Hb of CH2);
10.39 (s, H-N(2)). 13C-NMR (126 MHz, CDCl3) for 11 and
11’: d 27.88, 27.93, 32.0, 32.4, 34.6, 36.4, 54.7, 55.4, 59.6, 59.8,
64.9, 65.0, 80.9, 81.0, 126.07, 126.12, 127.1, 127.2, 127.5, 127.6,
128.1, 128.2, 128.27, 128.29, 129.0, 137.1, 137.2, 138.5, 138.7,
154.1, 154.2, 156.0, 156.1, 170.4, 170.7.
1
964, 915, 739, 697, 640 cm-1. H-NMR (500 MHz, DMSO-d6):
d 2.19 (dd, J = 16.9; 2.9 Hz, Ha-C(4)); 2.51–2.59 (m, Me-N
(1), Ha-C(7)); 2.84 (s, Me-N(2)); 2.89 (dd, J = 16.9; 8.5 Hz,
Hb-C(4)); 2.95–3.03 (m, Hb-C(7), H-C(5)); 3.57–3.64
(m, H-C(6)); 4.91 (d, J = 12.9 Hz, Ha of CH2); 4.95 (d,
J = 13.1 Hz, Hb of CH2); 7.15–7.35 (m, 10H of Ph, NH). 13C-
NMR (126 MHz, DMSO-d6): d 28.7, 30.6, 36.6, 43.2, 54.5,
64.9, 65.1, 126.0, 127.2, 127.6, 128.1, 128.3, 129.1, 137.3,
139.1, 156.1, 169.3.
Benzyl ((S)-1-((S)-1,2-dimethyl-5-oxopyrazolidin-3-yl)-2-phenylethyl)
carbamate (10’). To a solution of 6’ (294 mg, 0.833 mmol) in
anhydrous DMF (10 mL) under argon was added tBuOK
(94 mg, 0.833 mmol) followed by addition of MeI (52 mL,
0.833 mmol) and the resulting mixture was stirred at room
temperature for 2 h. Volatile components were evaporated
in vacuo and the residue was purified by CC (EtOAc). Fractions
containing the product 10’ were combined and volatile compo-
nents evaporated in vacuo. Yield: 250 mg (81%) of white solid;
mp 143–149 ꢀC. [a]Dr.t. = –80.3 (c = 0.28, CHCl3). (C21H25N3O3
requires: C, 68.64; H, 6.86; N, 11.44. found C, 67.92; H, 6.46; N,
11.40); EI-HRMS: m/z = 368.1968 (MH+); C21H26N3O3 requires:
m/z = 368.1969 (MH+); nmax 3302, 3059, 3031, 2952, 2856, 2789,
1716, 1682, 1603, 1533, 1496, 1454, 1411, 1386, 1364, 1328,
1249, 1121, 1087, 1042, 1025, 970, 935, 912, 848, 746, 697 cm-1.
1H-NMR (500 MHz, DMSO-d6): d 2.26 (dd, J = 16.8; 2.6 Hz,
Ha-C(4)); 2.56 (s, Me-N(1)); 2.60 (dd, J = 13.9; 10.8 Hz,
Ha-C(7)); 2.76 (dd, J= 14.1; 3.8 Hz, Hb-C(7)); 2.83 (s, Me-N(2));
2.96 (dd, J = 16.9; 9.3 Hz, Hb-C(4)); 3.09–3.15 (m, H-C(5));
3.66–3.75 (m, H-C(6)); 4.91 (d, J = 12.9 Hz, Ha of CH2);
4.95 (d, J = 13.0 Hz, Hb of CH2); 7.15–7.34 (m, 10H of Ph,
NH). 13C-NMR (126 MHz, DMSO-d6): d 28.5, 30.8, 35.3,
43.7, 55.6, 63.9, 64.8, 126.0, 127.1, 127.5, 128.1, 128.3,
129.1, 137.4, 138.9, 156.3, 169.3.
(R)-tert-Butyl 5-((S)-1-(((benzyloxy)carbonyl)amino)-2-phenylethyl)-
2-methyl-3-oxopyrazolidine-1-carboxylate (12) and (S)-tert-butyl
5-((S)-1-(((benzyloxy)-carbonyl)amino)-2-phenylethyl)-2-methyl-3-
oxopyrazolidine-1-carboxylate (12’). To a solution of epimeres
11/11’ (180 mg, 0.41 mmol, 11:11’= 1:0.5) in anhydrous DMF
(10 mL) were added K2CO3 (57 mg, 0.41 mmol) and MeI (77 mL,
1.23 mmol) and the resulting mixture was stirred at room temper-
ature for 24 h. Volatile components were evaporated in vacuo and
the residue was purified by CC (EtOAc/petroleum ether = 1:1).
Fractions containing the products were combined and volatile
components evaporated in vacuo to give the mixture of products
12/12’ in a ratio of 1:0.5, respectively. Yield: 181 mg (97%;
12:12’= 1:0.5) of colorless oil. [a]rD.t. = –16.3 (c = 0.19, CHCl3).
EI-HRMS: m/z =454.2332 (MH+); C25H32N3O5 requires:
m/z = 454.2336 (MH+). nmax 3315, 2978, 2932, 1690, 1530,
1497, 1455, 1415, 1393, 1368, 1324, 1294, 1240, 1160, 1143,
1
1109, 1045, 1029, 850, 737, 697, 674 cm-1. H-NMR (500 MHz,
Benzyl ((S)-1-((R)-1,2-dimethyl-5-oxopyrazolidin-3-yl)-2-phenylethyl)
carbamate (10). To a solution of 7 (100 mg, 0.283 mmol) in
MeOH (5 mL) were added HCHO (1.26 mL, 17 mmol, o = 37%
in H2O) and AcOH (100 mL, 1.747 mmol). After stirring at
room temperature for 1 h, NaCNBH3 (113 mg, 1.7 mmol)
was added and the resulting mixture was stirred for 1 h at
room temperature. Volatile components were evaporated
DMSO-d6) for 12: d 1.44 (s, tBu); 2.36 (dd, J = 16.9; 10.4Hz,
Ha-C(4)); 2.62 (dd, J = 13.7; 10.0 Hz, Ha-C(7)); 2.76–2.83 (m,
Hb-C(7)); 2.97 (s, Me-N(2)); 3.00 (dd, J = 17.6; 9.9 Hz, Hb-C
(4)); 3.75–3.87 (m, H-C(6)); 4.36 (dd, J = 8.7; 6.3 Hz, H-C(5));
4.94 (s, CH2); 7.14 (d, J = 6.8 Hz, 1H of Ph); 7.19–7.36 (m,
9H of Ph); 7.46 (d, J = 9.2 Hz, NH). 1H-NMR (500 MHz,
Chirality DOI 10.1002/chir

ꢀ
GROsELJ ET AL.
546
DMSO-d6) for 12’: d 1.48 (s, tBu); 2.68 (dd, J = 13.9;
11.7 Hz, Ha-C(7)); 4.47 (dd, J = 9.1; 3.8 Hz, H-C(5)); 4.91
(d, J = 13.0 Hz, Ha of CH2); 4.94 (d, J = 12.9 Hz, Hb of
CH2). 13C-NMR (126 MHz, CDCl3) for 12 and 12’: d
27.77, 27.80, 31.7, 33.0, 33.1, 33.2, 35.9, 36.1, 55.1, 55.7,
60.3, 61.2, 64.9, 65.1, 81.7, 81.8, 126.06, 126.13, 127.0,
127.4, 127.5, 127.7, 128.0, 128.16, 128.23, 128.3, 129.1,
137.0, 137.2, 138.5, 138.7, 155.8, 156.0, 156.4, 156.5,
170.3, 171.0.
1601, 1494, 1454, 1411, 1346, 1180, 1103, 1078, 1029, 918,
793, 744, 701 cm-1. 1H-NMR (500 MHz, DMSO-d6): d 2.39
(dd, J = 13.4; 8.8 Hz, Ha-C(7)); 2.43 (s, Me-N(1)); 2.45–2.57
(m, H2-C(4)); 2.70 (dd, J = 13.3; 4.9 Hz, Hb-C(7)); 2.69–2.76
(m, H-C(5)); 2.96 (dt, J = 9.1; 4.9 Hz, H-C(6)); 3.35 (br s, NH2);
7.09–7.35 (m, 5H of Ph); 9.28 (br s, H-N(2)). 13C-NMR
(126MHz, DMSO-d6): d 30.0, 39.8, 46.5, 53.1, 69.1, 125.9,
128.2, 129.1, 139.6, 172.0.
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((S)-1-((S)-2-methyl-5-
oxopyrazolidin-3-yl)-2-phenylethyl)thiourea (16’) and 1-(3,5-bis
(trifluoromethyl)phenyl)-3-((S)-1-((R)-2-methyl-5-oxopyrazolidin-3-
yl)-2-phenylethyl)thiourea (16). General Procedure 2 (GP2):
Prepared from a mixture of crude amine epimers 15/15’
(220 mg, 1 mmol; 15:15’ = 1:0.74), 3,5-bis(trifluoromethyl)-
phenyl isothiocyanate (13) (186 mL, 1 mmol), V(CH2Cl2) =
20 mL, MPLC (CHCl3/EtOH = 20:1).
Compound 16’: Elutes first. Yield: 120 mg (24%) of
white solid; mp 85-91 ꢀC. [a]Dr.t. = –78.9 (c = 0.19, CHCl3).
(C21H20F6N4OS requires: C, 51.43; H, 4.11; N, 11.42. found
C, 50.95; H, 3.62; N, 11.09); EI-HRMS: m/z = 491.1331 (MH+);
C21H21F6N4OS requires: m/z = 491.1335 (MH+); nmax 3217,
3063, 2925, 2854, 1678, 1527, 1472, 1456, 1381, 1340, 1274,
1170, 1124, 999, 966, 941, 885, 847, 698, 680 cm-1. 1H-
NMR (500 MHz, DMSO-d6): d 2.24 (dd, J = 17.2; 4.5 Hz,
Ha-C(4)); 2.58 (s, Me-N(1)); 2.78–2.92 (m, Hb-C(4),
Ha-C(7)); 2.98 (dd, J = 14.0; 5.7 Hz, Hb-C(7)); 3.27–3.33
(m, H-C(5)); 4.73–4.83 (m, H-C(6)); 7.18–7.24 (m, 1H
of Ph); 7.26–7.34 (m, 4H of Ph); 7.74 (s, 1H of Arl);
8.04 (d, J = 8.8 Hz, NH); 8.20 (s, 2H of Arl); 9.37 (s, NH); 10.16
(s, NH). 13C-NMR (126 MHz, DMSO-d6): d 31.6, 35.9, 48.0,
57.9, 64.3, 116.3, 121.9, 123.2 (q, J = 272.7 Hz), 126.3, 128.3,
129.0, 130.2 (q, J = 32.7 Hz), 138.2, 141.6, 171.6, 180.8.
Benzyl ((S)-1-((R)-1-methyl-5-oxopyrazolidin-3-yl)-2-phenylethyl)
carbamate (7) and benzyl ((S)-1-((S)-1-methyl-5-oxopyrazolidin-3-
yl)-2-phenylethyl)-carbamate (7’). To a solution of epimeres
12/12’ (90 mg, 0.2 mmol, 12:12’ = 1:0.5) in anhydrous
CH2Cl2 (5 mL) was added TFA (3mL) and the resulting mix-
ture was stirred at room temperature for 5 h. Volatile compo-
nents were evaporated in vacuo, the residue was dissolved in
EtOAc (150 mL) and washed with NaHCO3 (aq. sat., 10 mL).
The organic phase was dried over anhydrous Na2SO4, filtered,
and volatile components evaporated in vacuo to give crude
mixture of epimers 7/7’ in a ratio of 1:0.48, respectively.
Yield: 46 mg (66%) of white solid.
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((S )-1-((R )-1-methyl-5-
oxopyrazolidin-3-yl)-2-phenylethyl)thiourea (14). General
Procedure 2 (GP2): Prepared from 8 (39 mg, 0.178 mmol),
3,5-bis(trifluoromethyl)phenyl isothiocyanate (13) (33 mL,
0.178 mmol), V(Et2O) = 10 mL, CC (1. EtOAc/petroleum
ether = 1:1 (to elute the less polar impurities); 2. EtOAc
(to elute the product 14)). Yield: 56 mg (64%) of white
solid; mp 90–93 ꢀC. [a]Dr.t. = –74.1 (c = 0.085, CHCl3).
(C21H20F6N4OS requires: C, 51.43; H, 4.11; N, 11.42. found
C, 48.16; H, 3.62; N, 10.57); EI-HRMS: m/z = 491.1335
(MH+); C21H21F6N4OS requires: m/z = 491.1335 (MH+);
nmax 3289, 3202, 3065, 2930, 1666, 1538, 1496, 1472, 1456,
1383, 1339, 1275, 1170, 1125, 1031, 1001, 959, 934, 884,
Compound 16: Elutes second. Yield: 120 mg (24%) of white
solid; mp 89-96 ꢀC. [a]Dr.t.
= –13.6 (c = 0.12, CHCl3).
(C21H20F6N4OS requires: C, 51.43; H, 4.11; N, 11.42. found
C, 52.78; H, 4.24; N, 10.67); EI-HRMS: m/z = 491.1335
(MH+); C21H21F6N4OS requires: m/z = 491.1335 (MH+); nmax
3231, 3065, 2924, 2854, 1682, 1531, 1497, 1472, 1456, 1381,
1275, 1170, 1125, 1001, 986, 965, 883, 847, 726, 698, 680 cm-
1
848, 727, 699, 680, 656 cm-1. H-NMR (500MHz, DMSO-d6):
d 2.43 (dd, J = 16.5; 4.9 Hz, Ha-C(4)); 2.60 (dd, J = 16.4; 8.7 Hz,
Hb-C(4)); 2.75 (dd, J = 13.8; 9.3 Hz, Ha-C(7)); 2.89 (s, Me-N
(2)); 2.98 (dd, J = 14.2; 4.2 Hz, Hb-C(7)); 3.55–3.65 (m, H-C(5));
4.70–4.79 (m, H-C(6)); 5.97 (d, J = 7.8 Hz, H-N(1)); 7.14–7.33
(m, 5H of Ph); 7.73 (s, 1H of Arl); 8.15 (s, 2H of Arl); 8.20
(d, J = 8.8 Hz, NH); 9.96 (s, NH). 13C-NMR (126 MHz,
DMSO-d6): d 30.5, 34.3, 35.4, 55.3, 56.8, 116.3, 122.0,
123.2 (q, J = 272.6 Hz), 126.2, 128.1, 129.2, 130.2
(q, J = 32.7 Hz), 138.0, 141.6, 170.3, 180.6.
1
1. H-NMR (500 MHz, DMSO-d6): d 2.26 (dd, J = 17.2, 3.7 Hz,
Ha-C(4)); 2.53 (s, Me-N(1)); 2.76–2.90 (m, Ha-C(7), Hb-C(4));
3,02 (dd, J = 13.8; 2.7 Hz, Hb-C(7)); 3.14–3.22 (m, H-C(5));
4.72–4.81 (m, H-C(6)); 7.15–7.23 (m, 1H of Ph); 7.25–7.33
(m, 4H of Ph); 7.73 (s, 1H of Arl); 8.16 (s, 2H of Arl);
8.24 (d, J =8.9 Hz, NH); 9.47 (s, NH); 9.97 (s, NH). 13C-NMR
(126 MHz, DMSO-d6): d 31.1, 35.7, 47.6, 56.3, 66.3, 116.2,
121.9, 123.2 (q, J= 272.8 Hz), 126.2, 128.2, 129.1, 130.2
(q, J = 32.8 Hz), 138.2, 141.6, 172.1, 180.6.
(R)-5-((S)-1-Amino-2-phenylethyl)-1-methylpyrazolidin-3-one (15)
and (S)-5-((S)-1-amino-2-phenylethyl)-1-methylpyrazolidin-3-one
(15’). General Procedure 1 (GP1): Prepared from a mixture
of epimers 6/6’ (354 mg, 1 mmol, 6:6’ = 1:0.74), Pd–C
(70 mg), V = 40 mL. Thoroughly dried crude mixture of
products 15/15’ was used in the following transformation
(see the preparation of 16 and 16’) without any
characterization.
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((S )-1-((R )-2-methyl-5-
oxopyrazolidin-3-yl)-2-phenylethyl)thiourea (16). General Proce-
dure 2 (GP2): Prepared from crude amine 15 (29 mg, 0.132 mmol),
3,5-bis(trifluoromethyl)phenyl isothiocyanate (13) (25 mL,
0.132 mmol), V(Et2O)= 10 mL, CC (CHCl3/EtOH = 30:1). Yield:
48 mg (75%) of white solid.
(R)-5-((S)-1-Amino-2-phenylethyl)-1-methylpyrazolidin-3-one (15).
General Procedure 1 (GP1): Prepared from 6 (213 mg,
0.60 mmol), Pd–C (50 mg), V = 30 mL. Thoroughly dried crude
product 15 was used in the following transformation (see the
preparation of 16). Yield: full conversion; colorless oil.
[a]rD.t. = +98.9 (c = 0.55, MeOH). EI-HRMS: m/z = 220.1449
(MH+); C12H18N3O requires: m/z = 220.1444 (MH+); nmax
3350, 3178, 3061, 3027, 2959, 2918, 2856, 2795, 1668,
Chirality DOI 10.1002/chir
(R)-5-((S)-1-Amino-2-phenylethyl)-1,2-dimethylpyrazolidin-3-one
(17). General Procedure 1 (GP1): Prepared from 10
(221 mg, 0.60 mmol), Pd–C (50 mg), V = 30 mL. Thoroughly
dried crude product 10 was used in the following transforma-
tions (see the preparation of 18) without any characteriza-
tion. Yield: full conversion; colorless oil.

SYNTHESIS OF PHENYLALANINE DERIVED PYRAZOLIDINONES
547
(S)-5-((S)-1-Amino-2-phenylethyl)-1,2-dimethylpyrazolidin-3-one (17’).
General Procedure 1 (GP1): Prepared from 10’ (142 mg,
0.386 mmol), Pd–C (40 mg), V = 30 mL. Thoroughly dried
crude product 10’ was used in the following transforma-
tions (see the preparation of 18’) without any characteriza-
tion. Yield: full conversion; colorless oil.
(4)); 3.01 (dd, J = 13.7; 2.9 Hz, Hb-C(7)); 3.09–3.17 (m, H-C(5));
4.71–4.79 (m, H-C(6)); 7.16–7.25 (m, 3H of Arl); 7.26–7.32
(m, 3H of Arl); 7.38 (d, J = 8.9 Hz, NH); 7.45–7.56 (m, 3H of
Arl); 7.70 (d, J = 7.8 Hz, 1H of Arl); 7.84 (d, J = 8.2 Hz, 1H of
Arl); 7.95 (d, J = 7.7 Hz, 1H of Arl); 9.40 (s, NH); 9.50 (s, NH).
13C-NMR (126 MHz, DMSO-d6): d 31.0, 35.8, 47.8, 56.9, 66.6,
122.8, 125.3, 125.6, 126.0, 126.2, 126.8, 128.0, 128.1, 129.3,
130.0, 133.9, 134.2, 138.5, 172.5, 182.3.
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((S)-1-((R)-1,2-dimethyl-5-
oxopyrazolidin-3-yl)-2-phenylethyl)thiourea (18). General Proce-
dure 2 (GP2): Prepared from 17 (140 mg, 0.6 mmol), 3,5-bis
(trifluoromethyl)phenyl isothiocyanate (13) (112 mL, 0.6 mmol),
V(Et2O) = 20 mL, CC (EtOAc). Yield: 180 mg (59%) of white
solid; mp 185–190 ꢀC. [a]Dr.t. = –45.0 (c = 0.12, CHCl3).
(C22H22F6N4OS requires: C, 52.38; H, 4.40; N, 11.11. found
C, 52.20; H, 4.33; N, 11.00); EI-HRMS: m/z = 505.1498
(MH+); C22H23F6N4OS requires: m/z = 505.1491 (MH+);
nmax 3292, 3101, 2934, 1658, 1635, 1601, 1523, 1473, 1455,
1385, 1338, 1273, 1229, 1182, 1123, 999, 970, 962, 925,
895, 880, 848, 754, 728, 698, 679, 644 cm-1. 1H-NMR
(500 MHz, DMSO-d6): d 2.33 (dd, J = 17.1; 2.9 Hz, Ha-C
(4)); 2.59 (s, Me-N(1)); 2.71 (dd, J = 14.1; 9.8 Hz, Ha-C(7));
2.89 (s, Me-N(2)); 2.93–3.05 (m, Hb-C(7), Hb-C(4)); 3.24–3.31
(m, H-C(5)); 4.61–4.74 (m, H-C(6)); 7.14–7.22 (m, 1H of Ph);
7.23–7.34 (m, 4H of Ph); 7.73 (s, 1H of Arl); 8.16 (s, 2H of Arl);
8.21 (d, J = 8.7 Hz, NH); 10.00 (s, NH). 13C-NMR (126 MHz,
1-((S )-1-((S )-2-Methyl-5-oxopyrazolidin-3-yl)-2-phenylethyl)-3-
(naphthalen-1-yl)thiourea (20’). General Procedure 2 (GP2):
Prepared from crude amine 15’ (45 mg, 0.204 mmol),
1-isothiocyanatonaphthalene (19) (40 mg, 0.204 mmol),
V(DMF)= 5 mL, CC (EtOAc). Yield: 42 mg (51%) of white solid;
mp 81-87 ꢀC. [a]Dr.t. = –93.0 (c= 0.10, CHCl3). (C23H24N4OS
requires: C, 68.29; H, 5.98; N, 13.85. found C, 67.88; H, 6.75;
N, 11.88); EI-HRMS: m/z= 405.1737 (MH+); C23H25N4OS
requires: m/z = 405.1744 (MH+); nmax 3205, 3058, 2957, 2928,
2858, 1662, 1596, 1519, 1494, 1454, 1438, 1388, 1343, 1267,
1247, 1192, 1166, 1094, 1045, 1014, 953, 924, 870, 779, 747,
699, 660, 606 cm-1. 1H-NMR (500 MHz, DMSO-d6): d 2.30
(dd, J = 17.2; 4.1 Hz, Ha-C(4)); 2.53 (s, Me-N(1)); 2.73–2.84
(m, Hb-C(4), Ha-C(7)); 2.88 (dd, J = 13.8; 5.6 Hz, Hb-C(7));
3.24–3.30 (m, H-C(5)); 4.77–4.86 (m, H-C(6)); 7.19–7.26
(m, 3H of Arl); 7.26–7.34 (m, 3H of Arl, NH); 7.44–7.57 (m, 3H
of Arl); 7.73 (d, J = 8.0 Hz, 1H of Arl); 7.84 (d, J = 8.2 Hz, 1H
of Arl); 7.91–7.98 (m, 1H of Arl); 9.29 (s, NH); 9.64 (s, NH).
13C-NMR (126 MHz, DMSO-d6): d 31.4, 36.0, 48.1, 58.4, 64.5,
122.9, 125.0, 125.6, 126.16, 126.21, 126.7, 128.0, 128.2, 129.1,
129.8, 133.9, 134.3, 138.4, 171.9, 182.4.
DMSO-d6):
d 28.5, 30.9, 35.1, 43.6, 56.9, 63.9, 116.2,
121.84, 123.2 (q, J = 272.9 Hz), 126.1, 128.1, 129.1, 130.2
(q, J = 32.6 Hz), 138.2, 141.6, 169.2, 180.5.
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((S)-1-((S)-1,2-dimethyl-5-
oxopyrazolidin-3-yl)-2-phenylethyl)thiourea (18’). General Pro-
cedure 2 (GP2): Prepared from 17’ (90 mg, 0.386 mmol),
3,5-bis(trifluoromethyl)phenyl isothiocyanate (13) (72 mL,
0.386 mmol), V(Et2O) = 20 mL, CC (EtOAc). Yield: 120 mg
(61%) of white solid; mp 86-92 ꢀC. [a]Dr.t. = –98.4 (c = 0.062, CHCl3).
(C22H22F6N4OS requires: C, 52.38; H, 4.40; N, 11.11. found C,
52.28; H, 4.12; N, 10.82); EI-HRMS: m/z = 505.1489 (MH+);
C22H23F6N4OS requires: m/z = 505.1491 (MH+); nmax 3306,
3091, 2928, 2857, 1656, 1603, 1530, 1473, 1456, 1421, 1383,
1336, 1274, 1170, 1123, 1031, 1000, 969, 941, 881, 847, 729, 698,
(R)-2-Methyl-5-oxo-N-phenyl-3-((S)-2-phenyl-1-(3-phenylureido)
ethyl)-pyrazolidine-1-carboxamide (23). General Procedure 2
(GP2): Prepared from crude amine 15 (66 mg, 0.30mmol),
phenyl isocyanate (21) (36 mL, 0.33mmol), V(DMF)= 10mL,
CC (EtOAc/petroleum ether = 1:1). Yield: 47 mg (34%) of white
solid; mp 173-177 ꢀC. [a]Dr.t. = –101.8 (c= 0.11, CHCl3).
(C26H27N5O3 requires: C, 68.25; H, 5.95; N, 15.31. found C,
68.07; H, 5.69; N, 15.16); EI-HRMS: m/z = 458.2182 (MH+);
C26H28N5O3 requires: m/z = 458.2187 (MH+); nmax 3336, 3057,
3030, 2927, 1761, 1723, 1700, 1651, 1597, 1545, 1497, 1442,
1386, 1310, 1292, 1214, 1190, 1078, 1030, 897, 750, 692 cm-1.
1H-NMR (500MHz, DMSO-d6): d 2.61 (dd, J = 13.8; 10.5Hz,
Ha-C(7)); 2.65 (d, J = 17.8Hz, Ha-C(4)); 2.81 (s, Me-N(1)); 3.09
(dd, J = 13.8; 2.7 Hz, Hb-C(7)); 3.28 (t, J = 7.9 Hz, H-C(5)); 3.54
(dd, J = 17.9; 8.7 Hz, Hb-C(4)); 3.76–3.88 (m, H-C(6)); 6.26
(d, J = 9.0 Hz, NH); 6.86 (t, J = 7.3 Hz, 1H of Ph); 7.11
(t, J = 7.4 Hz, 1H of Ph); 7.14–7.19 (m, 3H of Ph); 7.20–7.30
(m, 6H of Ph); 7.35 (t, J = 7.9 Hz, 2H of Ph); 7.54 (d, J = 7.8 Hz,
2H of Ph); 8.45 (s, NH); 10.03 (s, NH). 13C-NMR (126 MHz,
DMSO-d6): d 32.8, 36.1, 45.7, 52.8, 64.1, 117.6, 119.8, 121.1,
123.9, 126.1, 128.2, 128.6, 129.0, 129.1, 137.4, 138.8, 140.2,
147.0, 154.9, 174.4.
1
679 cm-1. H-NMR (500 MHz, DMSO-d6): d 2.36 (dd, J =16.7;
3.1 Hz, Ha-C(4)); 2.62 (s, Me-N(1)); 2.83 (dd, J= 14.0; 9.0 Hz,
Ha-C(7)); 2.90 (m, 4H, Me-N(2), Hb-C(7)); 2.97 (dd, J = 17.0;
9.5 Hz, Hb-C(4)); 3.31–3.38 (m, H-C(5)); 4.78–4.87 (m, H-C(6));
7.17–7.24 (m, 1H of Ph); 7.26–7.34 (m, 4H of Ph); 7.74 (s, 1H of
Arl); 7.89 (d, J= 9.0 Hz, NH); 8.17 (s, 2H of Arl); 10.07 (s, NH).
13C-NMR (126 MHz, DMSO-d6): d 28.6, 31.1, 35.8, 43.8, 57.8,
62.3, 116.4, 122.1, 123.2 (q, J= 272.7 Hz), 126.3, 128.3, 129.0,
130.2 (q, J= 32.7 Hz), 138.1, 141.6, 169.0, 180.9.
1-((S)-1-((R)-2-Methyl-5-oxopyrazolidin-3-yl)-2-phenylethyl)-3-
(naphthalen-1-yl)thiourea (20). General Procedure 2 (GP2):
Prepared from crude amine 15 (66 mg, 0.30 mmol),
1-isothiocyanatonaphthalene (19) (59 mg, 0.30 mmol),
V(DMF) = 10 mL, CC (EtOAc). Yield: 60 mg (49%) of white
(R)-2-methyl-5-oxo-3-((S)-2-phenyl-1-(3-(p-tolyl)ureido)ethyl)-N-
(p-tolyl)pyra-zolidine-1-carboxamide (24). General Procedure 2
(GP2): Prepared from crude amine 15 (66 mg, 0.30mmol),
c (42 mL, 0.33mmol), V(DMF) = 10 mL, CC (EtOAc/petroleum
ether = 1:1). Yield: 65 mg (44%) of white solid; mp 99–105 ꢀC.
[a]rD.t. = –79.3 (c = 0.14, CHCl3). (C28H31N5O3 requires:
C, 69.26; H, 6.43; N, 14.42. found C, 69.03; H, 7.17; N, 12.10);
EI-HRMS: m/z = 486.2496 (MH+); C28H32N5O3 requires:
m/z = 486.2500 (MH+); nmax 3269, 2953, 2921, 2856, 1719,
1651, 1597, 1513, 1454, 1406, 1311, 1286, 1210, 1122,
solid; mp 170-173 ꢀC. [a]Dr.t.
= –46.7 (c= 0.12, CHCl3).
(C23H24N4OS requires: C, 68.29; H, 5.98; N, 13.85. found C,
67.34; H, 6.15; N, 12.45); EI-HRMS: m/z = 405.1737 (MH+);
C23H25N4OS requires: m/z = 405.1744 (MH+); nmax 3365, 3147,
3056, 2957, 2857, 1698, 1594, 1519, 1494, 1454, 1444, 1389,
1369, 1340, 1266, 1239, 1190, 1079, 1040, 1008, 953, 900, 790,
772, 746, 732, 699, 639 cm-1. 1H-NMR (500 MHz, DMSO-d6): d
2.26 (dd, J = 17.0; 2.2 Hz, Ha-C(4)); 2.50 (s, Me-N(1)); 2.68
(dd, J = 13.3; 10.5Hz, Ha-C(7)); 2.79 (dd, J = 17.0; 9.0 Hz, Hb-C
Chirality DOI 10.1002/chir

ꢀ
GROsELJ ET AL.
548
1
1030, 811, 736, 699 cm-1. H-NMR (500 MHz, DMSO-d6): d
2.19 (s, Me); 2.27 (s, Me); 2.57–2.67 (m, Ha-C(7), Ha-C
(4)); 2.80 (s, Me-N(1)); 3.08 (dd, J = 13.6; 2.3 Hz, Hb-C
(7)); 3.26 (t, J = 8.1 Hz, H-C(5)); 3.52 (dd, J = 17.8; 8.6 Hz,
Hb-C(4)); 3.76–3.85 (m, H-C(6)); 6.19 (d, J = 9.0 Hz, NH);
6.97 (d, J = 8.3 Hz, 2H of Arl); 7.13–7.19 (m, 5H of Arl);
7.19–7.27 (m, 4H of Arl); 7.41 (d, J = 8.3 Hz, 2H of Arl);
8.33 (s, NH); 9.97 (s, NH). 13C-NMR (126MHz, DMSO-d6): d
20.3, 20.4, 32.9, 36.2, 45.6, 52.8, 64.1, 117.7, 119.9, 126.0, 128.2,
129.0, 129.1, 129.4, 129.8, 132.9, 134.8, 137.6, 138.8, 147.0,
155.0, 174.4.
(m, H-C(6)); 4.93 (dd, J= 14.6; 13.3 Hz, CH2); 7.13–7.32 (m, 10H
of Arl); 7.39 (d, J =9.1Hz, NH); 7.45–7.54 (m, 4H of Arl); 9.94
(s, NH). 13C-NMR (126 MHz, DMSO-d6): d 32.9, 35.6, 45.8,
55.5, 63.3, 65.0, 115.2, 121.5, 126.1, 127.0, 127.5, 128.1, 128.2,
129.1, 131.7, 137.1, 137.2, 138.7, 146.9, 156.5, 173.9.
Friedel-Crafts alkylation of 1-methylindole with trans-cinnamaldehyde.
To a solution of catalyst 7 (46 mg, 0.13 mmol) in a mixture of anhy-
drous CH2Cl2 (850 mL) and anhydrous iPrOH (150 mL) under
Argon at –41 ꢀC was added TFA (10 mL). The solution was stirred
for 10 minutes before the addition of trans-cinnamaldehyde (190
mL, 1.5 mmol). After stirring for an additional 20 minutes 1-
methylindole (64 mL, 0.50 mmol) was added. The resulting mix-
ture was stirred at -41 ꢀC for 48 h. The reaction mixture was trans-
ferred into a suspension of NaBH4 (1.5 g) in EtOH (5 mL) and
stirred at room temperature. After 1 h the suspension was treated
with saturated aqueous NaHCO3 (20 mL), and the mixture was
extracted with Et2O (30 mL). The organic phase was dried over
anhydrous Na2SO4 and passed through a plug of Silica gel 60
and washed with Et2O. Volatile components were evaporated in
vacuo and the residue was used for the determination of conver-
sion (1H-NMR(CDCl3)). No reaction took place.
Benzyl ((S)-1-((R )-1-((4-bromophenyl)carbamoyl)-2-methyl-5-
oxopyrazolidin-3-yl)-2-phenylethyl)carbamate (26). General
Procedure 2 (GP2): Prepared from 6 (71 mg, 0.20mmol),
4-bromophenyl isocyanate (25) (40 mg, 0.20 mmol),
V(CH2Cl2) = 5 mL, CC (EtOAc/petroleum ether = 1:2). Yield:
70mg (63%) of white solid; mp 52-55 ꢀC. [a]Dr.t. = –46.0
(c= 0.10, CHCl3). (C27H27BrN4O4 requires: C, 58.81; H,
4.94; N, 10.16. found C, 58.64; H, 4.81; N, 9.98); EI-HRMS:
m/z = 551.1285 (MH+); C27H28BrN4O4 requires: m/z = 551.1288
(MH+); nmax 3275, 3030, 2925, 1720, 1699, 1591, 1539, 1490,
1454, 1398, 1319, 1302, 1277, 1213, 1190, 1139, 1120, 1072,
1028, 1006, 823, 737, 697 cm-1. H-NMR (500 MHz, DMSO-d6):
1
Michael addition of dimethyl malonate to trans-b-nitrostyrene.
Dimethyl malonate (2.5 mmol, 292 mL) was added to a solu-
tion of catalyst 14, 16/16’, or 18/18’ (0.1 mmol, 10 mol%)
and trans-b-nitrostyrene (149 mg, 1 mmol) in toluene (3 mL)
at room temperature and the resulting mixture was stirred
for 48 h. The reaction mixture was passed through a plug
of Silica gel 60 (EtOAc/petroleum ether = 1:1). Volatile
components were evaporated in vacuo and the residue
was used for the determination of conversion (1H-NMR
(CDCl3)). No reaction took place.
d 2.50–2.61 (m, Ha-C(7), Ha-C(4)); 2.78 (s, Me-N(1)); 3.09
(dd, J = 13.6; 2.8 Hz, Hb-C(7)); 3.20 (t, J = 7.9 Hz, H-C(5)); 3.48
(dd, J = 17.9; 8.5 Hz, Hb-C(4)); 3.61–3.69 (m, H-C(6));
4.84 (d, J = 12.8Hz, Ha-CH2); 4.90 (d, J = 12.8 Hz, Hb-CH2);
7.12–7.15 (m, 2H of Arl); 7.17–7.21 (m, 3H of Arl); 7.21–7.32
(m, 5H of Arl); 7.44 (d, J = 9.2 Hz, NH); 7.53 (s, 4H of Arl); 9.89
(s, NH). 13C-NMR (126MHz, DMSO-d6): d 32.5, 36.1, 45.6,
54.8, 64.1, 65.1, 115.5, 122.0, 126.0, 127.2, 127.6, 128.1, 128.3,
129.1, 131.7, 136.9, 137.1, 138.8, 147.0, 156.1, 173.7.
Single crystal X-Ray structure analysis for compounds 9 and 18.
Single crystal diffraction data for compounds 9 and 18 have
been collected on an Agilent SuperNova dual source diffrac-
tometer with an Atlas detector at room temperature with Cu
Ka (1.54184 Å) and Mo Ka radiation (0.71073 Å), respec-
tively. The data were processed using CrysAlis PRO
software.48 Both structures were solved by direct methods,
using SIR9749. A full-matrix least-squares refinement on F2
was employed with anisotropic displacement parameters
for all non-hydrogen atoms. H atoms were placed at calcu-
lated positions and treated as riding. SHELXL97 software50
was used for structure refinement and interpretation.
Drawings of the structures were produced using ORTEP-3.51
The agreement factors after final refinement R and wR
for compound 18 were very high. Unfortunately we were
Benzyl ((S )-1-((S )-1-((4-bromophenyl)carbamoyl)-2-methyl-5-
oxopyrazolidin-3-yl)-2-phenylethyl)carbamate (26’). General
Procedure 2 (GP2): Prepared from 6’ (283mg, 0.80 mmol),
4-bromophenyl isocyanate (25) (160 mg, 0.80 mmol),
V(CH2Cl2) = 15 mL, CC (EtOAc/petroleum ether = 1:2).
Yield: 300 mg (68%) of white solid; mp 62-64 ꢀC. [a]Dr.t. = –20.8
(c= 0.12, CHCl3). (C27H27BrN4O4 requires: C, 58.81; H, 4.94;
N, 10.16. found C, 58.80; H, 4.64; N, 9.88); EI-HRMS:
m/z = 551.1286 (MH+); C27H28BrN4O4 requires: m/z = 551.1288
(MH+); nmax 3330, 3031, 2969, 1716, 1697, 1593, 1543, 1490,
1454, 1398, 1372, 1300, 1278, 1239, 1211, 1175, 1120, 1071,
1042, 1006, 948, 824, 793, 737, 697, 639 cm-1. 1H-NMR
(500 MHz, DMSO-d6): d 2.62–2.72 (m, Ha-C(7), Ha-C(4)); 2.76
(s, Me-N(1)); 2.85 (dd, J = 13.7; 3.9 Hz, Hb-C(7)); 3.27–3.33
(m, H-C(5)); 3.50 (dd, J = 17.7; 8.8 Hz, Hb-C(4)); 3.77–3.85
Scheme 2. Synthesis of pyrazolidin-3-one precursor, compound 4.
Chirality DOI 10.1002/chir

SYNTHESIS OF PHENYLALANINE DERIVED PYRAZOLIDINONES
549
not able to get better crystal and collect better diffraction
data. Structural and other crystallographic data for
compounds 9 and 18 have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC 917328 and CCDC
921756, respectively. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
chromatography or by re-crystallization gave pure diastereo-
mer 3. Finally, mesylation of 3 in pyridine gave 4 (70% yield),
the starting compound for the cyclizations into pyrazolidin-3-
ones (Scheme 2).
For the cyclization of mesylate 4, hydrazine, methylhydrazine,
and 1,2-dimethylhydrazine were selected. Reaction of 4 with
hydrazine (3 equivalents, r.t.) in methanol proceeded sluggishly
with incomplete conversion. Switching the solvent to CH2Cl2 and
increasing the excess of hydrazine (7 equivalents, r.t., 24 h)
yielded the desired pyrazolidin-3-one in full conversion as a
mixture of epimers 5/5’ in a ratio of 5:5’ = 62:38 (crude reaction
mixture) and in 57% isolated yields. Increasing the reaction
temperature resulted in decreasing yields. All attempts to sepa-
rate 5/5’ failed. Following the same reaction conditions, cycliza-
tion of 4 with methylhydrazine yielded two regioizomeric
pyrazolidinones each as a mixture of epimers, products 6/6’/
7/7’ in a ratio of 6:6’:7:7’= 35:26:26:13, respectively, and in
100% conversion. Chromatographic separation yielded pure
isomers 6, 6’, and 7 in 25%, 18%, and 10% yield, respectively.
Performing the reaction under identical conditions in
DMF did not significantly change the product ratio in
the direction of one isomer, furnishing pyrazolidinones
6/6’/7/7’ in a ratio of 6:6’:7:7’ = 21:24:34:21. Reaction of
4 with 1,2-dimethylhydrazine failed to give the expected
product (Scheme 3). The poor diastereoselectivity of the
formation of 5/5’, 6/6’, and 7/7’ implies the substitution
of mesylate group with hydrazine proceeded either via a
mixed SN1/SN2 mechanism, or alternatively, under basic
conditions, initial elimination of mesylate group takes
place, followed by Michael addition of hydrazine to a,b-un-
saturated ester with low diastereoselectivity and final cycli-
zation. The formation of two regioisomers in the reaction
of 4 with methylhydrazine was not unexpected.
RESULTS AND DISCUSSION
N-Cbz-protected L-phenylalanine 1 was converted into the
corresponding b-keto ester 246 in 43% yield via the addition
of Li-enolate of methyl acetate to the reactive imidazolide of
1. Subsequent reduction of 2 with NaBH4 in MeOH at –
5 ꢀC gave a mixture of b-hydroxy esters 3 and 3’47 in a ratio
of 3:3’ = 86:14 in 83% yield. Separation by column
Because, the configuration of the newly created C(5)
stereogenic centre in pyrazolidinones 5-7/5’-7’ could not
be established using NMR techniques (suitable crystals for
single crystal X-ray analysis could not be obtained) was
pyrazolidinone 7 first hydrogenated to give Cbz-deprotected
diamine 8 followed by cyclization with 1,1’-carbonyldiimidazole
(CDI) to give a new bicyclic heterocycle, compound 9, in
Scheme 3. Cyclization of mesylate 4 with hydrazine and methylhydrazine.
Scheme 4. Synthesis of bicycles 9/9’.
Chirality DOI 10.1002/chir

ꢀ
GROsELJ ET AL.
550
84% yield. Similarly, hydrogenation of a mixture of epimers
7/7’ (7:7’ = 57:43) gave an inseparable mixture of amines
8/8’, respectively, which were cyclized using CDI into
the corresponding and easily separable bicycles 9 and 9’
in 49% and 16% yield, respectively (Scheme 4). The struc-
ture of 9 was unambiguously determined by single crystal
X-ray analysis (Figure 1). The C(5) stereogenic center
forms the tip of the envelope of both pyrazolidinone and
imidazolidinone part of the bicyclic system, while the
remaining four atoms on each sides of the bicycle lie in
their respective planes. In pyrazolidinone part of the
molecule, the smaller substituent, H(5), adopts axial
position, while in the imidazolidinone part H(5) adopts
equatorial position (see the Supporting Information).
Having established the absolute configuration of com-
pound 7 (and therefore also of 7’) the absolute configuration
of pyrazolidinones 6/6’ was unambiguously determined
using chemical correlation with 7. Compound 7 was reduc-
tively methylated using formaldehyde and NaCNBH3 to form
1,2-dimethylpyrazolidinone 10 (41% yield). On the other hand,
pyrazolidinones 6 and 6’ were alkylated with iodomethane in
the presence of tBuOK to form 1,2-dimethylpyrazolidinones
10 and 10’ in 91% and 81% yield, respectively (Scheme 5).
Finally, using chemical correlation with 7, the absolute
configuration of pyrazolidinones 5/5’ was determined.
Inseparable mixture of epimeres 5/5’ (5:5’ = 70:30) were
first Boc-protected at N(1) position giving the correspond-
ing products 11/11’ in a ratio of 11:11’ = 67:33 and 54%
yield. Next, the mixture of 11/11’ was methylated using
MeI in the presence of K2CO3 which furnished the corre-
sponding Boc-N(1)-Me-N(2) protected pyrazolidinones 12/
12’ in a ratio of 12:12’ = 67:33 and 97% yield. Deprotection
of pyrazolidinones 12/12’ with TFA in CH2Cl2 gave
the corresponding pyrazolidinones 7/7’ in a ratio of
7:7’ = 68:32 and 66% yield. The relative ratio of the starting
pyrazolidinones 5/5’ was maintained through the chemi-
cal correlation (Scheme 6).
O2
C5
C6
C10
N1
N2
N3
C4
C9
C11
O1
C12
C7
C1
C3
C8
C13
C2
Fig. 1. Single crystal X-ray structure of compound 9.
Scheme 5. Chemical correlation of imidazolidinones 6/6’ with imidazolidinone 7.
Scheme 6. Chemical correlation of imidazolidinones 5/5’ with imidazolidinone 7.
Chirality DOI 10.1002/chir

SYNTHESIS OF PHENYLALANINE DERIVED PYRAZOLIDINONES
551
Having established the absolute configuration of all the
novel pyrazolidinones, a series of (thio)urea derivatives
was prepared to check their organocatalytic properties.
Diamine 8 (prepared by deprotection of 7) reacted with
3,5-bis(trifluoromethyl)phenyl isothiocyanate (13) selectively
with the primary amino group giving thiourea 14 in 64% yield.
Similarly, Cbz-deprotection of a mixture of epimers 6/6’
(6:6’ = 57:43) gave a mixture of amines 15/15’ followed by
reaction with isothiocyanate 13 to give after chromatographic
separation thioureas 16 and 16’ each in 24% yield,
respectively. Alternatively, thiourea 16 was prepared from pure
pyrazolidinone 6 via Cbz-deprotection into amine 15 and reac-
tion with isothiocyanate 13 in 75% yield. In a similar manner,
deprotection of 1,2-dimethylpyrazolidinones 10 and 10’ gave
the corresponding amines 17 and 17’, which were converted
with isothiocyanate 13 into thiourea derivatives 18 and 18’
in 59% and 61% yield, respectively (Scheme 7). The structure
of 18 was additionally confirmed by single crystal X-ray analy-
sis (Figure 2). As in the structure of compound 9, C(5) position
forms the tip of the envelope, the remaining four atoms of
pyrazolidinone ring lying in the plane of the envelope. H(5)
adopts equatorial position leaving the large C(5) substituent
in the axial position, thus minimizing the strain between
the large C(5) substituent and the Me-N(1) substituent52, the
pyramidalization53 of the N(1) pointing in the direction of the
large C(5) substituent (see the Supporting Information).
Further (thio)urea derivatives have been prepared. Thus
reaction of amines 15 and 15’, prepared by catalytic
hydrogenation of 6 and 6’, respectively, with 1-naphthyl
isothiocyanate (19) gave the corresponding thioureas 20
and 20’ in 49% and 51% yield, respectively. Interestingly, reac-
tions of 15 with more reactive isocyanates, phenyl isocyanate
(21) and 4-methylphenyl isocyanate (22), in slight excess
gave bis urea derivatives 23 and 24 in 34% and 44% yield,
respectively. Apparently, the hydrazidic N(2) position is
nucleophylic enough to react with more electrophilic isocya-
nates. Reactions with 4-bromophenyl isocyanate (25) were
repeated with Cbz-protected pyrazolidinones 6 and 6’ giving
the expected ureas 26 and 26’ in 63% and 68% yield, respec-
tively (Scheme 8).
Scheme 7. Synthesis of 3,5-bis(trifluoromethyl)phenyl derived thioureas.
Chirality DOI 10.1002/chir

ꢀ
GROsELJ ET AL.
552
The following trends have been noticed: (i) the H-C(5) and
C18
H-C(6) protons of the (5R)-epimers 5-7, 10-12, 16, 18,
20, 26 are slightly up-field shifted compared to their
corresponding (5S)-epimers 5’-7’, 10’-12’, 16’, 18’,
20’, 26’; (ii) the H-N(1) and/or H-N(2) protons of
(5S)-epimers 5’-7’, 11’ are slightly up-field shifted com-
pared to their (5R)-epimer 5-7, 11 counterparts; (iii)
Ha-C(4) and Hb-C(4) proton correlations are not 100%
reliable, though in most cases the (5R)-epimers have
these protons up-field shifted compared to respective
(5S)-epimers. In the case of bicycles 9/9, the only prop-
erty standing out is the difference in chemical shift
between Ha-C(4) and Hb-C(4) protons i.e. for 9 this
difference is ca. 1 ppm while for 9’ this difference is
ca. 0.4 ppm. Clearly, the Ha-C(4) proton of 9 must be up field
shifted due to the anisotropy caused by the benzyl group in
position 6. Furthermore, protons H-C(5) and H-C(6) of 9 appear
as multiplets, while in 9’ the corresponding protons appear as a
dublet of dublet and as a triplet, respectively. Other properties
did not give satisfactory correlations (Table 1).
C19
C34
C13
C27
C17
C29
C16
C8
C24
N4
N2
C14
N3
C6
F28
N5
C9
C11
C15
C10
F37
C22
C12
S1
F30
O7
C23
C21
F41
C20
F33
C35
F26
Fig. 2. Single crystal X-ray structure of compound 18.
Finally, selected pyrazolidinones have been tested as
potential organocatalysts. First, the cyclic secondary amine
7 has been tested as a potential covalent organocatalyst
in the Friedel-Crasfts alkylation of 1-methylindole with
cinnamaldehyde.54 Similarly as in recently reported iminium
Hoping to find a solid correlation, which would enable a
quick assignation of the absolute configuration of the newly
formed C(5) stereogenic centre, we looked at proton chemi-
cal shifts of pairs of isolated pyrazolidinone epimers, focusing
at pyrazolidin-3-one protons and H-C(6) proton (see Table 1).
Scheme 8. Synthesis of (thio)urea derivatives.
Chirality DOI 10.1002/chir

SYNTHESIS OF PHENYLALANINE DERIVED PYRAZOLIDINONES
553
TABLE 1. Selected chemical shifts (in ppm) of selected pyrazolidin-3-ones and bicycles 9/9’
Compound
H-N(1)
H-N(2)
Ha-C(4)
Hb-C(4)
H-C(5)
H-C(6)
5
5.45
5.28
–
9.08
9.01
9.37
9.32
–
2.18
2.24
2.13
2.22
2.37
–
3.42
3.58
2.97
3.11
3.36
3.50
2.99
3.12
4.29
4.45
4.36
4.47
3.18
3.30
3.27
3.34
3.13
3.27
3.20
3.28
4.21
4.09
3.70
3.80
3.65
3.74
3.67
3.76
3.60
3.70
a
5’
6
2.73
2.80
6’
–
7
5.81
5.75
–
2.27
2.46
a
a
7’
–
–
10
10’
11
11’
12
12’
16
16’
18c
18’
20
20’
26
26’
9c
–
–
2.19
2.26
2.89
2.96
2.88
2.95
–
–
10.49
10.39
–
2.38
3.91
a
a
–
–
–
–
2.36
3.00
3.81
a
a
a
–
–
–
–
–
b
2.26
2.24
2.33
2.36
2.26
2.30
2.55
2.67
2.03
2.32
2.83
2.85
2.99
2.97
2.79
2.78
3.48
3.50
3.01
2.68
4.76
4.78
4.67
4.82
4.75
4.81
3.65
3.81
4.15
3.80
b
–
–
–
–
–
–
–
–
–
–
–
b
b
–
–
–
–
9’
aOverlapped by other signals;
bcould not be determined unambiguously;
cstructure determined by single crystal X-ray crystallography.
reactive intermediates derived from imidazolidinone
organocatalysts,54–56 in the hipothetic reactive iminium
intermediate derived from 7 and cinnamaldehyde the
bulky group in position 5 could serve as the directing
group for the attack of the nucleophile (1-methylindole)
while the Me group in position 2 would impose the
trans-configuration around the C = N bond to minimize
the nonbonding interactions.52 Unfortunately, no conversion
took place, plausibly due to the choice of the substituent in
position 2 and/or too bulky substituent in position 5 (for com-
parison see Ref. 29) (Figure 3, top).
Next, compounds 14, 16, 16’ 18, and 18’ have been
tested as potential non-covalent organocatalyst in the Michael
addition of dimethyl malonate to trans-b-nitrostyrene.57
Similarly as Takemoto’s bifunctional catalyst,57 where a
tertiary amine and thiourea functionalities attached to a chiral
scaffold serve to activate both nucleophilic and electrophilic
partner in the selected stereoselective transformation, respec-
tively, pyrazolidinones 14, 16, 16’ 18, and 18’ poses,
similarly, a thiourea and a tertiary or a secondary amine
(as part of the cyclic hydrazine derivative) positioned next
to each other to catalyze the Michael addition. Disappointingly,
no reaction took place presumably because of steric/
conformational constrains present in our tested catalysts
and/or because of the different basicity of our substituted
hydrazine part of the catalysts compared to Takemoto’s tertiary
amine part of the catalyst (Figure 3, bottom).
Fig. 3. Selected pyrazolidinones tested as potential organocatalysts.
CONCLUSIONS
In this report, it has been shown, that C(5) substituted
pirazolidin-3-ones can be prepared from suitably protected
a-amino acid derivatives. In a model reaction, N-Cbz-protected
L-phenylalanine was first transformed into the corresponding
keto ester, followed by reduction of the keto group, mesylation
and cyclization with hydrazine and methylhydrazine. The
configurations of the C(5)-epimeric pyrazolidinones were
confirmed unambiguously by single crystal X-ray analysis and
via step by step chemical correlation/interconversion. A series
of pyrazolidinone (thio)urea derivatives has been synthesized,
Chirality DOI 10.1002/chir

ꢀ
GROsELJ ET AL.
554
20. Yang K-S, Lain J-C, Lin C-H, Chen K. Diastereoselective [3 + 2] cycloaddi-
tions of a camphor-derived chiral N-acryloylhydrazide with nitrile oxides:
the preparation of optically pure 2-isoxazolines. Tetrahedron Lett
2000;41:1453–1456.
21. Yang K-S, Chen K. Diastereoselective Baylis-Hillman Reactions: The
Design and Synthesis of a Novel Camphor-Based Chiral Auxiliary. Org
Lett 2000;2:729–731.
22. Sibi MP, Stanley LM, Nie X, Venkatraman L, Liu M, Jasperse CP. The
Role of Achiral Pyrazolidinone Templates in Enantioselective Diels-Alder
Reactions: Scope, Limitations, and Conformational Insights. J Am Chem
Soc 2007;129:395–405.
characterized, and eventually tested as potential organocatalysts,
although without success. Correlation of proton chemical shifts
of pairs of epimeric pirazolidinones suggest that a simple
determination of the configuration of the newly created
C(5)-stereogenic centre might be possible also for other
properly protected a-amino acid derived pyrazolidinones.
Additionally, pyrazolidinones derived from a-amino acids
could be used to create a library of novel bicyclic deriva-
tives of type 9/9’ or could be selectively derivatized at
positions 1, 2, 4 and 6.
23. Sibi MP, Manyem S, Palencia H. Fluxional Additives:
A
Second
Generation Control in Enantioselective Catalysis.
J Am Chem Soc
2006;128:13 660–13 661.
LITERATURE CITED
24. Sibi MP, Venkatraman L, Liu M, Jasperse CP. A new approach to
enantiocontrol and enantioselectivity amplification: chiral relay in Diels-
Alder reactions. J Am Chem Soc 2001;123:8444–8445.
1. Elguero J. Pyrazoles. In: Katritzky AR, Rees CW, Scriven EFV, editors. Com-
prehensive Heterocyclic Chemistry II. Oxford: Elsevier; 1996; Vol 3, p 1–75.
2. Varvounis G, Fiamegos Y, Pilidis G. Pyrazol-3-ones part 1: Synthesis and
applications. Adv Heterocycl Chem 2001;80:73–156.
25. Lemay M, Aumand L, Ogilvie WW. Design of a conformationally rigid
hydrazide organic catalyst. Adv Synth Catal 2007;349:441–447.
3. Eicher T, Hauptmann S. The Chemistry of Heterocycles, 2nd ed.;
Weinheim: Wiley-VCH, 2003.
26. Lemay M, Trant J, Ogilvie WW. Hydrazide-catalyzed 1,3-dipolar nitrone
cycloadditions. Tetrahedron 2007;63:11 644–11 655.
4. Marchand-Brynaert J, Ghosez L. Non b-lactam analogs of penicillins and
cephalosporins. In: Lukacs G, Ohno M, editors. Recent Progress in the
Chemical Synthesis of Antibiotics; Berlin: Springer; 1990. p 727–794.
5. Hanessian S, McNaughton-Smith G, Lombart H-G, Lubell WD. Design
and synthesis of conformationally constrained amino acids as versatile
scaffolds and peptide mimetics. Tetrahedron 1997;53:12 789–12 854.
27. Lemay M, Ogilvie WW. Mechanistic Studies of Hydrazide-Catalyzed
Enantioselective Diels-Alder Reactions. J Org Chem 2006;71:4663–4666.
28. Lemay M, Ogilvie WW. Aqueous Enantioselective Organocatalytic Diels-
Alder Reactions Employing Hydrazide Catalysts. A New Scaffold for
Organic Acceleration. Org Lett 2005;7:4141–4144.
29. Gould E, Lebl T, Slawin AMZ, Reid M, Smith AD. Structural effects in
pyrazolidinone-mediated organocatalytic Diels-Alder reactions. Tetrahedron
2010;66:8992–9008.
6. Konaklieva MI, Plotkin BJ. Bioisosters of b-lactams as anti-infectives. Curr
Med Chem Anti-Infect Agents 2003;2:287–302.
7. White HL, Howard JL, Cooper BR, Soroko FE, McDermed JD, Ingold KJ,
Maxwell RA. A novel inhibitor of gamma-aminobutyrate aminotransferase
with anorectic activity. J Neurochem 1982;39:271–273.
8. Kawai K, Hasegawa J, Shiojiri H, Nozawa Y, Tsurumi K, Fujimura H.
Interaction of BW755C, a potent inhibitor of lipoxygenase and cyclo-
oxygenase, with mitochondrial cytochrome oxidase. Experientia
1985;41:490–492.
30. Brazier JB, Cavill JL, Elliott RL, Evans G, Gibbs TJK, Jones IL, Platts JA,
Tomkinson NCO. The a-effect in cyclic secondary amines: new scaf-
folds for iminium ion accelerated transformations. Tetrahedron
2009;65:9961–9966.
31. Evans GJS, White K, Platts JA, Tomkinson NCO. Computational study of
iminium ion formation: effects of amine structure. Org Biomol Chem
2006;4:2616–2627.
9. Cucurou C, Battioni JP, Thang DC, Nam NH, Mansuy D. Mechanisms of
inactivation of lipoxygenases by phenidone and BW755C. Biochemistry
1991;30:8964–8970.
32. Cavill JL, Elliott RL, Evans G, Jones IL, Platts JA, Ruda AM,
Tomkinson NCO. The a-effect in iminium ion catalysis. Tetrahedron
2005;62:410–421.
10. Kosower EM, Hershkowitz E. (Ramot University Authority for Applied
Research and Industrial Development Ltd., Israel). assignee. Preparation
of 1H,7H-Pyrazolo[1,2-a]pyrazole-1,7-dione for treatment of cognitive
dysfunction. Application: IL IL patent 1990–94658 94658. 1994 19900607.
11. Jungheim LN, Sigmund SK, Fisher JW. Bicyclic pyrazolidinones. A new
class of antibacterial agent based on the b-lactam model. Tetrahedron Lett
1987;28:285–288.
12. Jungheim LN, Sigmund SK. 1,3-Dipolar cycloaddition reactions of
pyrazolidinium ylides with acetylenes. Synthesis of a new class of
antibacterial agents. J Org Chem 1987;52:4007–4013.
33. Sibi MP, Soeta T. Enantioselective Conjugate Addition of Hydrazines to
a,b-Unsaturated Imides. Synthesis of Chiral Pyrazolidinones. J Am Chem
Soc 2007;129:4522–4523.
34. Fernández M, Reyes E, Vicario JL, Badía D, Carrillo L. Organocatalytic
Enantioselective Synthesis of Pyrazolidines, Pyrazolines and Pyrazolidinones.
Adv Synth Catal 2012;354:371–376.
35. Sibi MP, Kawashima K, Stanley LM. Diels-Alder Cycloaddition Strategy for
Kinetic Resolution of Chiral Pyrazolidinones. Org Lett 2009;11:3894–3897.
36. Suarez A, Downey CW, Fu GC. Kinetic resolutions of azomethine imines
via copper-catalyzed [3 + 2] cycloadditions. J Am Chem Soc 2005;127:11
244–11 245.
37. Shintani R, Soh Y-T, Hayashi T. Rhodium-Catalyzed Asymmetric Arylation
of Azomethine Imines. Org Lett 2010;12:4106–4109.
38. Chan A, Scheidt KA. Direct Amination of Homoenolates Catalyzed by
13. Claramunt RM, Elguero J. The chemistry of pyrazolidinones. A review.
Org Prep Proc Int 1991;23:273–320.
14. Ternansky RJ, Draheim SE, Pike AJ, Counter FT, Eudaly JA, Kasher JS.
Structure-activity relationship within a series of pyrazolidinone antibacterial
agents. 2. Effect of side-chain modification on in vitro activity and pharmaco-
kinetic parameters. J Med Chem 1993;36:3224–3229.
N-Heterocyclic Carbenes. J Am Chem Soc 2008;130:2740–2741.
39. Presset M, Mohanan K, Hamann M, Coquerel Y, Rodriguez J. 1,3-Dipolar
Cycloaddition of Hydrazones with a-Oxo-ketenes: A Three-Component
Stereoselective Entry to Pyrazolidinones and an Original Class of
Spirooxindoles. Org Lett 2011;13:4124–4127.
40. Rueping M, Maji MS, Kuecuek HB, Atodiresei I. Asymmetric Bronsted
Acid Catalyzed Cycloadditions-Efficient Enantioselective Synthesis of
Pyrazolidines, Pyrazolines, and 1,3-Diamines from N-Acyl Hyrazones and
Alkenes. Angew Chem Int Ed 2012;51:12 864–12 868.
41. Blanchard WB, Britton TC, Varie DL; (Eli Lilly and Co., USA). assignee.
Enantioselective synthesis of pyrazolidin-3-one derivatives. Application:
US US patent 1993-153843 5399708. 1995 19931112.
42. Ahmed O, Hitchcock PB, Young DW. Investigation of a route to ibotenic
acid analogues via a reduced pyroglutamate template. Org Biomol Chem
2006;4:1596–1603.
15. Kosower EM, Radkowsky AE, Fairlamb AH, Croft SL, Neal RA. Bimane
cyclic esters, possible stereologs of trypanothione as antitrypanosomal
agents. Bimanes 29. Eur J Med Chem 1995;30:659–671.
16. Wang S-G, Tsai HR, Chen K. Lewis acid mediated diastereoselective
allylation of camphorpyrazolidinone derived a-ketoamides. Tetrahedron
Lett 2004;45:6183–6185.
17. Fan CL, Lee W-D, Teng N-W, Sun Y-C, Chen K. Epoxidation of Chiral
Camphor N-Enoylpyrazolidinones with Methyl(trifluoromethyl)dioxirane
and Urea Hydrogen Peroxide/Acid Anhydride: Reversal of
Stereoselectivity. J Org Chem 2003;68:9816–9818.
18. Yang K-S, Chen K. A facile and highly diastereoselective aziridination of
chiral camphor N-enoylpyrazolidinones with N-aminophthalimide. J Org
Chem 2001;66:1676–1679.
19. Lin CH, Yang KS, Pan JF, Chen K. Diastereoselective conjugate addition of
thiols to camphor pyrazolidinone derived chiral a,b-unsaturated carbonyls:
synthesis of b-mercaptocarboxylic acid derivatives. Tetrahedron Lett
2000;41:6815–6819.
43. Otto A, Ziemer B, Liebscher J. Synthesis of chiral 4-(o-hydroxyalkyl)
pyrazolidin-3-ones by ring-chain transformation of a-alkylidene lactones
with hydrazines. Eur J Org Chem 1998;11:2667–2672.
Chirality DOI 10.1002/chir

SYNTHESIS OF PHENYLALANINE DERIVED PYRAZOLIDINONES
555
44. Bohrisch J, Faltz H, Paetzel M, Liebscher J. Optically active 5-
(hydroxyalkyl)- and 5-(aminoalkyl)pyrazolidin-3-ones by ring-chain trans-
formation of a,b-unsaturated lactones or lactams with hydrazines. Liebigs
Ann 1996;10:1581–1585.
52. Quinkert G, Egert E, Griesinger C. Aspects of organic chemistry: struc-
ture. Basel: Verlag Helvetica Chimica Acta; 1996, 430 pp.
53. The pyramidality of the N-atom is given as the distance of N from the
plane of its three bonding atom partners.
45. Tamborini L, Pinto A, Smith TK, Major LL, Iannuzzi MC, Cosconati S,
Marinelli L, Novellino E, Lo Presti L, Wong PE and others. Synthesis and
Biological Evaluation of CTP Synthetase Inhibitors as Potential Agents for the
Treatment of African Trypanosomiasis. ChemMedChem 2012;7:1623–1634.
46. Mansour TS, Evans CA. Decarboxylative carbon acylation of malonates
with aminoacylimidazolides mediated by Lewis acids. Synth Commun
1990;20:773–781.
54. Austin JF, MacMillan DWC. Enantioselective Organocatalytic Indole
Alkylations. Design of a New and Highly Effective Chiral Amine for
Iminium Catalysis. J Am Chem Soc 2002;124:1172–1173.
ꢀ
55. Seebach D, Groselj U, Badine DM, Schweizer WB, Beck AK. Isolation
and X-ray structures of reactive intermediates of organocatalysis
with diphenylprolinol ethers and with imidazolidinones. A survey and
comparison with computed structures and with 1-acyl-imidazolidinones:
the 1,5-repulsion and the geminal-diaryl effect at work. Helv Chim Acta
2008;91:1999–2034.
47. Devant RM, Radunz HE. A novel short and efficient asymmetric synthesis
of statine analogs. Tetrahedron Lett 1988;29:2307–2310.
48. Agilent Technologies. CrysAlis PRO. Version Version 1.171.35.11.
Yarnton, Oxfordshire, England: Agilent Technologies; 2011.
ꢀ
56. Groselj U, Schweizer WB, Ebert M-O, Seebach D. 5-benzyl-3-
methylimidazolidin-4-one-derived reactive intermediates of
49. Altomare A, Burla MC, Camalli M, Cascarano GL, Giacovazzo C, Guagliardi
A, Moliterni AGG, Polidori G, Spagna R. SIR97: a new tool for crystal struc-
ture determination and refinement. J Appl Cryst 1999;32:115–119.
organocatalysis - a comforting resemblance of X-ray, NMR, and DFT
solid-phase, liquid-phase, and gas-phase structures. Helv Chim Acta
2009;92:1–13.
50. Sheldrick GM. A short history of SHELX. Acta Cryst A 2008;A64:112–122.
51. Farrugia LJ. ORTEP-3 for windows - a version of ORTEP-III with a graph-
ical user interface (GUI). J Appl Crystallogr 1997;30:568.
57. Okino T, Hoashi Y, Takemoto Y. Enantioselective Michael Reaction of
Malonates to Nitroolefins Catalyzed by Bifunctional Organocatalysts.
J Am Chem Soc 2003;125:12 672–12 673.
Chirality DOI 10.1002/chir