A convenient approach to the synthesis of ω-heterocyclic amino acids from carboxy lactams through ring-chain transformation; part 1: Synthesis of (2S)-/(2R)-2-amino-4-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)butyric acid

Article abstract of DOI:10.1055/s-2005-872166

A general method is reported for the synthesis of co-heterocyclic α-amino acids, which involves preparation of enaminone intermediates from thiolactams, followed by reaction with dinucleophiles, resulting in a single-step condensation and ring-chain trans

Full text of DOI:10.1055/s-2005-872166

PAPER
2765
A Convenient Approach to the Synthesis of w-Heterocyclic Amino Acids from
Carboxy Lactams through Ring–Chain Transformation; Part 1: Synthesis of
(2S)-/(2R)-2-Amino-4-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)butyric Acid
S
ynthesis of (2
S
)
a
2
R
)-2-A
m
k
ino-4-(1-ar
e
s
H
-pyr
h
a
zol-3-yl)butyric
A
K
c
id . Singh,a Neelima Sinha,a,1 Sanjay Jain,*a,1 Mohammad Salman,a Fehmida Naqvi,b Nitya Anand*a
a
Medicinal Chemistry Division, New Drug Discovery Research, Ranbaxy Laboratories Limited, R&D II, Plot # 20, Sector 18,
Udyog Vihar Industrial Area, Gurgaon 122001, India
Fax +91(20)25171329; E-mail: sanjayjain@lupinpharma.com; E-mail: nityaanand@satyam.net.in
Department of Chemistry, Jamia Millia Islamia, New Delhi 110015, India
b
Received 13 April 2005; revised 3 May 2005
and its higher analogs, simply by extending the lactam
ring size.
Abstract: A general method is reported for the synthesis of w-het-
erocyclic a-amino acids, which involves preparation of enaminone
intermediates from thiolactams, followed by reaction with dinu-
cleophiles, resulting in a single-step condensation and ring–chain
transformation to the desired w-heterocyclic a-amino acids after
deprotection of amine and carboxylic group. The reaction steps pre-
serve the chirality of the parent-substituted lactam. The method is
illustrated by the synthesis of (2S)- and (2R)-2-amino-4-(1-aryl-/
1,5-diaryl-1H-pyrazol-3-yl)butyric acids.
Lactams have been the subject of much study in our
laboratory8 to explore the scope that lactams and their ac-
tivated forms offer for generating molecular diversity due
to their ability to undergo facile nucleophilic, electrophilic
and cycloaddition reactions. Lactams also provide easy
access to reactive species such as enaminones (1, X =
CH), and their aza analogues (1, X = N), which are useful
intermediates for building aromatic, carbocyclic and het-
erocyclic rings on the azacycloalkane platform (Path A),
and for ready entry to side chain w-functionalized alkyl
heterocycles by ring-chain transformation reaction (Path
B).8 The path B transformation seemed to provide a useful
core reaction strategy for the synthesis of w-substituted a-
amino acids with much possibility for introduction of
structural variations and creation of molecular diversity
(Figure 1). This strategy has been used successfully for
the development of methods for the synthesis of optically
active w-heterocyclic-a-amino acids.
Key words: amino acids, ring opening, chirality, lactams, hydroge-
nations
Unnatural amino acids, particularly a-amino acids, have
enriched medicinal chemistry research in many ways.
They have been used2 extensively in peptide analoguing
to modify conformational flexibility, to enhance enzymat-
ic stability and to improve pharmacodynamic and bio-
availability characteristics of medicinally important
peptides. Numerous therapeutically important compounds
with an unnatural amino acid moiety in their structures
have been reported.3–7 Current developments in genomics
and proteomics hold promise of providing a myriad of vir-
gin new protein targets whose actions will be open for
modulation by small molecules. Unnatural amino acids
have the potential of providing structurally and function-
ally unique chemo-types to cater to both small molecule
needs and related peptides for drug research. As a conse-
quence, the development of versatile new methodology
for the preparation of proteinogenic, natural, and unnatu-
ral amino acids in optically pure form has emerged as a
highly significant and challenging synthetic endeavor.
Many reviews describing synthesis and applications of
unnatural a-amino acids are available.3 The main objec-
tive of the present study was to design novel analogs of
natural amino acids carrying modified electronic interac-
tion sites in the side chain which could influence interac-
tions with the receptors/acceptor molecules and may
further elucidate biological recognition. A short path syn-
thesis is described in this paper, which is unique in its ver-
satility to afford optically active unnatural a-amino acids
Path A
El Nu
O
R1
Path B
Path A
X
N
R
Nu
X
R1
N
R
Nu
X
RHN
R1
Path B
3
1
2
Figure 1
The starting methyl L-thiopyroglutamate 4 was prepared
from L-glutamic acid following the procedure described
in the literature.9 The thiolactam 4 was subjected to sulfur
extrusion reaction by following the literature procedure10
to afford enaminones 5a–c in fair yields depending upon
the electrophile chosen (Scheme 1, Table 1). The enami-
nones 5 exhibited the required spectral and analytical pro-
files.
Enaminones 5 were then subjected to regiospecific ring-
chain transformation11 by reactions with hydroxylamine,
hydrazine and phenylhydrazine in protic solvents like
MeOH or EtOH at reflux for a period of 12–36 hours to
afford the desired (2S)-(+)-2-benzylamino-4-(5-aryl-isox-
SYNTHESIS 2005, No. 16, pp 2765–2771
x
x.
x
x
.
2
0
0
5
Advanced online publication: 12.08.2005
DOI: 10.1055/s-2005-872166; Art ID: T04905SS
© Georg Thieme Verlag Stuttgart · New York

2766
R. K. Singh et al.
PAPER
ArCOCH2Br
Ph3P, Et3N
Table 1 Physical Data of Various Synthesized Intermediates
O
Ar
Compounda
Yield (%)b
Mp (°C)
Optical rotationc
CO2Me
S
CO2Me
MeCN–CH2Cl2
r.t., 24 h
N
N
24
[a]D
Bn
Bn
4
5a; Ar = C6H5
5b; Ar = 4-FC6H4
5c; Ar = 4-MeOC6H4
5a
5b
5c
33
48
23
59
79
78
94
93
87
83
78
79
82
93
74
76
65
89
97
83
Oil
+144.1
+187.2
+245
101-102
78-79
63-64
Oil
Scheme 1
6a
+24.6
+10.3
+19.3
+14.3
+15.3
+1.5
azol-3-yl)butyric acid methyl ester 6a,b and (2S)-(+)-2-
benzylamino-4-(5-aryl-1-(un)substituted-1H-pyrazol-3-
yl)butyric acid methyl ester 7a–e in 78–94% yields
(Scheme 2, Table 1). The structure of products 6 and 7
was confirmed by spectroscopic methods (see experimen-
tal section). The differentiation between the isomeric
structures of 7c–e is possible by 1H NMR (ArH signals are
shifted downfield) and 13C NMR (g-CH2 and 3-Cpyra sig-
nals downfield shifted) and such observations have been
reported earlier.11
6b
7a
Oil
7b
7c
Oil
Oil
7d
7e
Oil
Oil
+14.5
+25.0
+21.1
+20.9
+33.9
-141
-198
-211
-27.0
-23.0
-22.7
8a
157-159
120-121
133-134
128-129
Oil
NH2OH
EtOH
O
N
NHBn
8b
8c
Ar
reflux
7–15 h
CO2Me
6a; Ar = C6H5
6b; Ar = 4-FC6H4
5a–c
8d
11a
11b
11c
12
R
RNHNH2
EtOH
N
N
NHBn
Ar
reflux
8–18 h
92-93
79-80
154-155
Oil
CO2Me
7a; R = H, Ar = C6H5
7b; R = H, Ar = 4-FC6H4
7c; R = C6H5, Ar = C6H5
7d; R = C6H5, Ar = 4-MeOC6H4
7e; R = 4-MeOC6H4, Ar = 4-MeOC6H4
13
Scheme 2
14
160-161
a For spectroscopic and analytical data, see the experimental section.
b Yields of analytically pure products.
With 1-arylpyrazolyl amino acid esters 7c–e, N-deben-
zylation occurred easily in cyclohexene12 in the presence
of Pd-C as catalyst to give (2S)-(+)-2-amino-4-(1,5-aryl-
1H-pyrazol-3-yl)butyric acid methyl ester 8b–d, whereas
with (2S)-(+)-2-benzylamino-4-(5-aryl-1H-pyrazol-3-
yl)butyric acid methyl ester 7a, N-debenzylation was eas-
iest in formic acid and Pd-C to afford (2S)-(+)-2-amino-4-
(5-aryl-1H-pyrazol-3-yl)butyric acid methyl ester 8a in
good yield (Scheme 3, Table 1). However, other catalytic
transfer hydrogenation conditions and classical catalytic
hydrogenation did not deprotect nitrogen so cleanly. N-
Debenzylation of (2S)-(+)-2-benzylamino-4-(5-aryl-isox-
azol-3-yl)butyric acid methyl esters 6a,b could not be
achieved successfully as isoxazolyl rings underwent fis-
sion under various experimental conditions attempted.
Development of experimental conditions to circumvent
this problem is under study and will form part of future re-
ports. The acidic hydrolysis of the esters 8a–d afforded
the desired (2S)-(+)-2-amino-4-[5-aryl-1-(un)substituted-
1H-pyrazol-3-yl]butyric acids 9a–d in good yields, which
were isolated as hydrochloride salts (Scheme 3, Table 2).
c For concentration of compound and solvent used, see the experimen-
tal section.
R
HCOOH or
N
N
NH2⋅HCl
7a, c–e
Ar
10% Pd-C
CO2Me
reflux, 4–18 h
8a–d
6N HCl
reflux
4–6 h
R
N
N
NH2
CO2H
Ar
9a–d
a; R = H, Ar = C6H5
b; R = C6H5, Ar = C6H5
c; R = C6H5, Ar = 4-MeOC6H4
d; R = 4-MeOC6H4, Ar = 4-MeOC6H4
Scheme 3
Following a similar sequence of reactions, methyl D-thio-
pyroglutamate 10 was converted to (2R)-(–)-2-amino-4-
Synthesis 2005, No. 16, 2765–2771 © Thieme Stuttgart · New York

PAPER
Synthesis of (2S)-/(2R)-2-Amino-4-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)butyric Acid
2767
(5-phenyl-1H-pyrazol-3-yl)butyric acid (15) as shown in Table 2 Physical Data of Unnatural a-Amino Acids Synthesized
Scheme 4 (Table 2). The compounds 9a–d and 15 were
Compounda Yield (%)b Mp (°C)
Optical rotationc Purity
[a]D
fully characterized on the basis of complementary spec-
troscopic (1H NMR and MS) and analytical data. The
preservation of the chirality in each reaction sequence of
the synthesis was established by the comparing specific
(% ee)d
24
9a
9b
9c
9d
88
96
90
97
90
240-241
215-216
190-191
118-119
234-235
+34.8
+4.1
99.1
98.7
24
optical rotation [a]D of each intermediate product with
their antipodes. Finally the enantiomeric excesses was es-
tablished by chiral HPLC analysis and it was found to be
> 98% ee.
+11.5
+19.9
-32.9
98.1
98.5
15
98.9
The successful exploration of methyl L- and D-thiopyro-
glutamate as synthons for the generation of novel w-het-
erocyclic a-amino acids have been achieved to pave the
way for synthesis of close analogues of a proteinogenic
amino acids such as histidine. The same methodology can
be employed in the synthesis of unnatural b- and g-amino
acids and even its higher analogues simply by extending
the lactam ring size, and varying the position of carboxyl
group on the lactam ring on which we are presently work-
ing in our laboratory.
a For spectroscopic and analytical data, see the experimental section.
b Yields of analytically pure products.
c For concentration of compound and solvent used, see the experimen-
tal section.
d Determined by chiral HPLC analysis using Kromasil C18 column.
150 mm) analytical column. The compounds were eluted at a flow
rate of 1.5 mL/min and detected at 240 nm, using pH 4.5 buffer–
MeOH (70:30) as eluent. The chiral purity and enantiomeric excess-
es of the amino acids were determined by chiral HPLC analysis us-
ing Chiradex (5 m, 4.6 × 25 mm) column. The compounds were
eluted at flow rate of 0.5 mL/min and detected at 220 nm, using pH
3.0 buffer–MeCN (30:70) as eluent. Elemental analyses were car-
ried out with a Perkin Elmer 2400 analyzer and values found were
within 0.4% of theoretical values.
O
(i)
Ar
S
CO2Me
CO2Me
N
N
Bn
Bn
11a; Ar = C6H5
11b; Ar = 4-ClC6H4
10
11c; Ar = 4-MeOC6H4
(S)-(+)-1-Benzyl-5-(2-oxo-2-phenylethylidene)pyrrolidine-2-
carboxylic Acid Methyl Ester (5a); Typical Procedure
To a solution of thiolactam 4 (24.9 g, 100 mmol) in anhyd MeCN
(48 mL), phenacyl bromide (24.9 g, 125 mmol) was added and the
reaction mixture was stirred for 8 h at r.t. The solid, which separated
out, was dissolved by addition of anhyd CH2Cl2 (500 mL) and
stirred for 0.5 h at the same temperature. Ph3P (39.3 g, 150 mmol)
and Et3N (30.3 g, 300 mmol) were then added one after another, and
the reaction mixture was stirred for another 24 h at the same temper-
ature. Solvents were removed under reduced pressure and the resi-
due was dissolved in EtOAc (500 mL), washed with H2O (3 × 100
mL), brine (1 × 100 mL), dried (Na2SO4) and filtered. The filtrate
was concentrated under reduced pressure to give a crude product,
which was purified by column chromatography over silica gel
(100–200 mesh) using EtOAc–hexanes (2:8) as eluent to give 5a as
a colorless thick oil; yield: 11.0 g (33%); [a]D +144.1 (c = 1,
MeOH).
IR (CH2Cl2): 1742, 1695 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.00–2.03 (m, 4 H), 3.34 (q, J =
9.2 Hz, 1 H), 3.69 (s, 3 H), 4.35 (d, J = 15.0 Hz, 1 H), 4.75 (d, J =
15.1 Hz, 1 H), 5.98 (s, 1 H), 7.19–7.81 (m, 10 H).
(ii)
(iii)
HN
N
O N
NHBn
NHBn
Ph
Ar
CO2Me
CO2Me
12; Ar = 4-MeOC6H4
13
(iv)
HN
N
HN
N
NH2⋅HCl
(v)
NH2
Ph
Ph
CO2Me
CO2H
24
14
15
Scheme 4 Reagents and conditions: (i) ArCOCH2Br, Ph3P, Et3N,
MeCN–CH2Cl2, r.t., 24 h; (ii) H2NOH, MeOH or EtOH, reflux, 10 h;
(iii) NH2NH2, MeOH or EtOH, reflux, 12 h; (iv) HCOOH, 10% Pd-
C, reflux, 8 h; (v) 6 N HCl, reflux 6 h.
MS: m/z = 336 [M + 1].
Melting points were recorded on a Büchi B-540 melting point appa-
ratus. Compounds were routinely checked for their purity on silica
gel 60 F254 TLC plates and their spots were visualized by exposing
them to iodine vapor, UV lamp or by spraying the plates with
Dragendorff’s or ninhydrine or KMnO4 reagents. IR spectra (lmax in
cm–1) were recorded on Perkin Elmer Paragon-1000 PC instrument
and NMR (300 MHz) spectra were recorded on Bruker 300-DRX
spectrometer as solutions using TMS as internal standard, and
chemical shifts are expressed in d units. Mass spectra were recorded
on API-3000 LC-MS/MS instrument using direct inlet system under
positive ion electrospray ionization source and GC-MS spectra
were recorded on Finnigan NAT-GCQ instrument. Optical rotations
were taken on Autopol-III instrument. The purity of final products
was determined by HPLC analysis on Kromasil (C18, 5 mL, 4.6 ×
Anal. Calcd for C21H21NO3 (335.40): C, 75.20; H, 6.31; N, 4.18.
Found: C, 75.38; H, 6.53; N, 4.29.
(S)-(+)-1-Benzyl-5-[2-(4-fluorophenyl)-2-oxoethylidene]pyrrol-
idine-2-carboxylic Acid Methyl Ester (5b)
Isolated as a white solid in 48% yield; mp 101–102 °C; [a]D
+187.2 (c = 0.5, MeOH).
24
IR (KBr): 1744, 1691, 1595, 1504 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.21–2.36 (m, 2 H), 3.28–3.69 (m,
2 H), 3.71 (s, 3 H), 4.21 (dd, J = 3.1, 6.0 Hz, 1 H), 4.37 (d, J = 15.8
Hz, 1 H), 4.76 (d, J = 15.8 Hz, 1 H), 5.93 (s, 1 H), 7.05 (t, J = 8.7
Hz, 2 H), 7.23–7.41 (m, 5 H), 7.80–7.84 (m, 2 H).
Synthesis 2005, No. 16, 2765–2771 © Thieme Stuttgart · New York

2768
R. K. Singh et al.
PAPER
MS: m/z = 354 [M + 1].
25–30 °C with stirring and the resulting reaction mixture was re-
fluxed for 10 h. Solvent was removed under reduced pressure; the
residue was suspended in the EtOAc (100 mL) and washed with
20% aq NaHCO3 (2 × 20 mL), water (1 × 20 mL), brine (1 × 20 mL),
dried (Na2SO4) and filtered. The filtrate was concentrated under re-
duced pressure to obtain crude product which was purified by col-
umn chromatography over silica gel (100–200 mesh) using EtOAc–
hexanes (1:1) as eluent to give 6a as an off-white solid; yield: 3.19
g (59%); mp 63–64 °C; [a]D24 +24.6 (c = 0.5, MeOH).
Anal. Calcd for C21H20FNO3 (353.39): C, 71.37; H, 5.70; N, 3.96.
Found: C, 71.25; H, 5.65; N, 3.72.
(S)-(+)-1-Benzyl-5-[2-(4-methoxyphenyl)-2-oxoethylidene]pyr-
rolidine-2-carboxylic Acid Methyl Ester (5c)
Isolated as a white solid in 23% yield; mp 78–79 °C; [a]D +245
(c = 1.19, MeOH).
24
IR (KBr): 1745, 1690, 1630, 1599, 1219, 1160 cm–1.
IR (KBr): 1728, 1573, 1450 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.19–2.37 (m, 2 H), 3.27–3.33 (m,
2 H), 3.69 (s, 3 H), 3.83 (s, 3 H), 4.18 (dd, J = 3.3, 6.0 Hz, 1 H), 4.34
(d, J = 15.8 Hz, 1 H), 4.74 (d, J = 15.6 Hz, 1 H), 5.96 (s, 1 H), 6.88
(t, J = 2.7 Hz, 2 H), 7.23–7.39 (m, 5 H), 7.80 (t, J = 2.4 Hz, 2 H).
1H NMR (300 MHz, CDCl3): d = 1.72–2.14 (m, 2 H), 2.21 (br s, 1
H), 2.84–2.92 (m, 2 H), 3.37 (dd, J = 3.0, 6.0 Hz, 1 H), 3.66 (d, J =
14.0 Hz, 1 H), 3.75 (s, 3 H), 3.87 (d, J = 14.0 Hz, 1 H), 6.31 (s, 1
H), 7.26–7.38 (m, 5 H), 7.43–7.50 (m, 3 H), 7.74–7.77 (m, 2 H).
MS: m/z = 366 [M + 1].
MS: m/z = 351 [M + 1].
Anal. Calcd for C22H23NO4 (365.42): C, 72.31; H, 6.34; N, 3.83.
Found: C, 72.13; H, 6.73; N, 3.82.
Anal. Calcd for C21H22N2O3 (350.41): C, 71.98; H, 6.33; N, 7.99.
Found: C, 72.11; H, 6.16; N, 7.61.
(R)-(–)-1-Benzyl-5-(2-oxo-2-phenylethylidene)pyrrolidine-2-
carboxylic Acid Methyl Ester (11a)
(S)-(+)-2-Benzylamino-4-[5-(4-fluorophenyl)isoxazol-3-yl]bu-
tyric Acid Methyl Ester (6b)
Isolated as a thick oil in 74% yield; [a]D24 –141 (c = 1, MeOH).
Isolated as a thick oil in 79% yield; [a]D24 +10.3 (c = 1, MeOH).
IR (CHCl3): 1742, 1695, 1630, 1578, 1537 cm–1.
IR (CH2Cl2): 1734, 1617, 1511, 1452, 1234 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.04 (br s, 1 H), 2.16–2.32 (m, 3
H), 3.21 (q, J = 9.0 Hz, 1 H), 3.60 (s, 3 H), 4.35 (d, J = 15.0 Hz, 1
H), 4.75 (d, J = 15.0 Hz, 1 H), 5.98 (s, 1 H), 7.22–7.81 (m, 10 H).
1H NMR (300 MHz, CDCl3): d = 1.99–2.20 (m, 2 H), 2.25 (br s, 1
H), 2.90 (dd, J = 3.0, 9.0 Hz, 2 H), 3.39 (dd, J = 3.0, 6.0 Hz, 1 H),
3.69 (d, J = 14.0 Hz, 1 H), 3.78 (s, 3 H), 3.90 (d, J = 14.0 Hz, 1 H),
6.28 (s, 1 H), 7.16–7.22 (m, 2 H) 7.26–7.38 (m, 5 H), 7.43–7.50 (m,
2 H).
MS: m/z = 336 [M + 1].
Anal. Calcd for C21H21NO3 (335.40): C, 75.20; H, 6.31; N, 4.18.
Found: C, 75.09; H, 6.16; N, 3.97.
MS: m/z = 369 [M + 1].
Anal. Calcd for C21H21FN2O3 (368.40): C, 68.46; H, 5.75; N, 7.60.
Found: C, 68.63; H, 5.83; N, 7.71.
(R)-(–)-1-Benzyl-5-[2-(4-chlorophenyl)-2-oxoethylidene]pyrro-
lidine-2-carboxylic Acid Methyl Ester (11b)
Isolated as a white solid in 76% yield; mp 92–93 °C; [a]D –198
(c = 1.01, MeOH).
24
(S)-(+)-2-Benzylamino-4-(5-phenyl-1H-pyrazol-3-yl)butyric
Acid Methyl Ester (7a)
IR (KBr): 1749, 1690, 1627, 1587, 1570, 1500 cm–1.
Isolated as a thick oil in 78% yield; [a]D24 +19.3 (c = 0.7, MeOH).
1H NMR (300 MHz, CDCl3): d = 2.14–2.34 (m, 2 H), 3.27 (q, J =
9.1 Hz, 1 H), 3.62 (d, J = 9.0 Hz, 1 H), 3.67 (s, 3 H), 4.17 (d, J = 7.0
Hz, 1 H), 4.33 (d, J = 15.1 Hz, 1 H), 4.71 (d, J = 15.0 Hz, 1 H), 5.88
(s, 1 H), 7.20 (d, J = 6.5 Hz, 2 H), 7.23–7.34 (m, 5 H), 7.70 (d, J =
6.5 Hz, 2 H).
IR (CH2Cl2): 1733, 1570, 1464, 1201 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.91–2.11 (m, 2 H), 2.15 (br s, 1
H), 2.84 (t, J = 7.0 Hz, 2 H), 3.33 (q, J = 6.0 Hz, 1 H), 3.66 (d, J =
14.0 Hz, 1 H), 3.74 (s, 3 H), 3.86 (d, J = 14.0 Hz, 1 H), 6.33 (s, 1
H), 7.20–7.43 (m, 8 H), 7.72 (d, J = 8.0 Hz, 2 H), 13.35 (br s, 1 H).
MS: m/z = 370 [M + 1].
MS: m/z = 350 [M + 1].
Anal. Calcd for C21H20ClNO3 (369.84): C, 68.20; H, 5.45; N, 3.79.
Found: C, 68.57; H, 5.66; N, 3.81.
Anal. Calcd for C21H23N3O2 (349.43): C, 72.18; H, 6.63; N, 12.03.
Found: C, 71.95; H, 6.81; N, 11.86.
(R)-(–)-1-Benzyl-5-[2-(4-methoxyphenyl)-2-oxoethylidene]pyr-
(S)-(+)-2-Benzylamino-4-[5-(4-fluorophenyl)-1H-pyrazol-3-
yl]butyric Acid Methyl Ester (7b)
rolidine-2-carboxylic Acid Methyl Ester (11c)
Isolated as a white solid in 65% yield; mp 79–80 °C; [a]D –211
(c = 1.04, MeOH).
24
Isolated as a thick oil in 94% yield; [a]D24 +14.3 (c = 1, MeOH).
IR (CH2Cl2): 1734, 1526, 1508, 1453, 1223 cm–1.
IR (KBr): 1744, 1629, 1580, 1543, 1500 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.04–2.10 (m, 2 H), 2.20 (br s, 1
H), 2.81–2.86 (m, 2 H), 3.32 (dd, J = 6.0, 9.0 Hz, 1 H), 3.66 (d, J =
14.0 Hz, 1 H), 3.72 (s, 3 H), 3.90 (d, J = 14.2 Hz, 1 H), 6.27 (s, 1
H), 7.06–7.12 (m, 2 H), 7.29–7.36 (m, 5 H), 7.68–7.73 (m, 2 H),
13.50 (br s, 1 H).
1H NMR (300 MHz, CDCl3): d = 2.04–2.22 (m, 1 H), 2.28–2.35 (m,
1 H), 3.31 (dd, J = 3.0, 9.0 Hz, 1 H), 3.64 (dd, J = 3.1, 9.0 Hz, 1 H),
3.68 (s, 3 H), 3.82 (s, 3 H), 4.17 (dd, J = 3.0, 6.0 Hz, 1 H), 4.34 (d,
J = 15.0 Hz, 1 H), 4.73 (d, J = 15.0 Hz, 1 H), 5.95 (s, 1 H), 6.86 (d,
J = 9.0 Hz, 2 H), 7.22–7.38 (m, 5 H), 7.79 (d, J = 9.0 Hz, 2 H).
MS: m/z = 368 [M + 1].
MS: m/z = 366 [M + 1].
Anal. Calcd for C21H22FN3O2 (367.42): C, 68.65; H, 6.04; N, 11.44.
Found: C, 69.01; H, 6.11; N, 11.25.
Anal. Calcd for C22H23NO4 (365.42): C, 72.31; H, 6.34; N, 3.83.
Found: C, 72.09; H, 6.56; N, 3.67.
(S)-(+)-2-Benzylamino-4-(1,5-diphenyl-1H-pyrazol-3-yl)bu-
tyric Acid Methyl Ester (7c)
(S)-(+)-2-Benzylamino-4-(5-phenylisoxazol-3-yl)butyric Acid
Methyl Ester (6a): Ring–Chain Transformation Reaction; Gen-
eral Procedure
Hydroxylamine hydrochloride (1.1 g, 15.4 mmol) was added to a
solution of enaminone 5a (5.2 g, 15.4 mmol) in EtOH (20 mL) at
Isolated as a thick oil in 93% yield; [a]D24 +15.3 (c = 0.076, MeOH).
IR (CH2Cl2): 3419, 2909, 1739, 1617, 1510 cm–1.
Synthesis 2005, No. 16, 2765–2771 © Thieme Stuttgart · New York

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Synthesis of (2S)-/(2R)-2-Amino-4-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)butyric Acid
2769
1H NMR (300 MHz, CDCl3): d = 2.02–2.14 (m, 2 H), 2.15 (br s, 1
H), 2.81–2.92 (m, 2 H), 3.41 (dd, J = 6.0, 9.1 Hz, 1 H), 3.67 (d, J =
12.0 Hz, 1 H), 3.73 (s, 3 H), 3.86 (d, J = 12.0 Hz, 1 H), 6.20 (s, 1
H), 7.20–7.34 (m, 15 H).
13C NMR (75 MHz, CDCl3): d = 172.0, 152.9, 145.8, 139.7, 137.2,
129.1, 129.0, 128.5, 127.0, 126.0, 118.8, 106.9, 60.6, 52.2, 50.4,
33.8, 25.0.
N-Debenzylation of 7 and 13; General Method
Method 1: A mixture of N-benzyl amino acid esters 7 or 13 (1.0 g),
10% Pd-C (1.0 g), formic acid (50 mL) was refluxed with stirring
for 4–12 h. After completion of reaction, reaction mixture was
cooled to r.t. and filtered through Celite bed, washed with EtOH (2
× 5 mL) and the combined filtrate was concentrated under reduced
pressure to afford crude amino acid esters. These crude amino acid
esters were purified by treating them with ethereal HCl, or their N-
Boc derivative was prepared and purified by column chromatogra-
phy over silica gel (200–400 mesh), which upon treatment with
methanolic HCl afforded the pure amino acid ester as hydrochloride
salt.
MS: m/z = 426 [M + 1].
Anal. Calcd for C27H27N3O2 (425.52): C, 76.21; H, 6.40; N, 9.87.
Found: C, 76.19; H, 6.33; N, 9.62.
(S)-(+)-2-Benzylamino-4-[5-(4-methoxyphenyl)-1-phenyl-1H-
pyrazol-3-yl]butyric Acid Methyl Ester (7d)
N-Boc Protection; General Method
Isolated as a thick oil in 87% yield; [a]D24 +1.5 (c = 1, MeOH).
To a stirred solution of crude amino acid ester (1 equiv) in CH2Cl2
(20 mL) were added t-Boc anhydride (1.1 equiv) and Et3N (1.1
equiv) at 0 °C. The resulting reaction mixture was stirred for 1–3 h
at the same temperature. After completion of reaction, the reaction
mixture was diluted with CH2Cl2 (50 mL) and washed with chilled
10% NaHCO3 (3 × 50 mL), brine (1 × 50 mL), dried (Na2SO4) and
filtered. The filtrate was concentrated under reduced pressure to
give a crude product, which was purified by column chromatogra-
phy over silica gel (100–200 mesh) using 0.5% MeOH–CHCl3 as
eluent to afford the pure N-Boc derivative of amino acid ester.
IR (CH2Cl2): 3410, 2920, 1744, 1611, 1501 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.12–2.14 (m, 2 H), 2.25 (br s, 1
H), 2.75–2.91 (m, 2 H), 3.50 (br s, 1 H), 3.67 (d, J = 12.0 Hz, 1 H),
3.73 (s, 3 H), 3.79 (s, 3 H), 3.91 (d, J = 14.0 Hz, 1 H), 6.21 (s, 1 H),
6.79–6.82 (m, 2 H), 7.08–7.11 (m, 2 H), 7.28–7.37 (m, 10 H).
MS: m/z = 456 [M + 1].
Anal. Calcd for C28H29N3O3 (455.55): C, 73.82; H, 6.42; N, 9.22.
Found: C, 73.61; H, 6.11; N, 9.35.
N-Boc Deprotection; General Method
(S)-(+)-2-Benzylamino-4-[1,5-bis-(4-methoxyphenyl)-1H-pyra-
zol-3-yl]butyric Acid Methyl Ester (7e)
To a stirred solution of pure N-Boc amino acid ester in MeOH (5
mL) was added 1 M MeOH–HCl (5 equiv) at 0 °C and resulting re-
action mixture stirred at the same temperature until TLC indicated
complete disappearance of the starting material (10–12 h). Solvent
was removed under reduced pressure to afford a solid material,
which was dried under reduced pressure to afford the corresponding
amino acid esters as HCl salts.
Isolated as a thick oil in 83% yield; [a]D24 +14.5 (c = 0.5, MeOH).
IR (CH2Cl2): 1733, 1614, 1517, 1249 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.03–2.13 (m, 2 H), 2.20 (br s, 1
H), 2.78–2.88 (m, 2 H), 3.38–3.43 (m, 1 H), 3.66 (d, J = 12.1 Hz, 1
H), 3.72 (s, 6 H), 3.80 (s, 3 H), 3.86 (d, J = 14.0 Hz, 1 H), 6.20 (s, 1
H), 6.79–6.84 (m, 4 H), 7.09–7.36 (m, 9 H).
Method 2: A mixture of N-benzyl amino acid esters 7 or 13 (1.0 g),
10% Pd-C (0.5 g), cyclohexene (100 mL) was refluxed with stirring
for 6–18 h. After completion of reaction, reaction mixture was
cooled to r.t. and filtered through a Celite bed, washed with EtOH
(2 × 5 mL) and the filtrate was concentrated under reduced pressure
to afford the crude amino acid esters which were purified as de-
scribed above in Method 1.
MS: m/z = 456 [M + 1].
Anal. Calcd for C29H31N3O4 (485.57): C, 71.73; H, 6.43; N, 8.65.
Found: C, 71.62; H, 6.55; N, 8.47.
(R)-(–)-2-Benzylamino-4-[5-(4-methoxyphenyl)isoxazol-3-
yl]butyric Acid Methyl Ester (12)
Isolated as a white hydrochloride salt in 89% yield; mp 154–155 °C;
(S)-(+)-2-Amino-4-(5-phenyl-1H-pyrazol-3-yl)butyric Acid
Methyl Ester (8a) (Method 1)
[a]D24 –27.0 (c = 1, MeOH).
IR (KBr): 3464, 2924, 2722, 2577, 1741, 1538, 1451 cm–1.
Isolated as a white hydrochloride salt from compound 7a in 78%
yield; mp 157–159 °C; [a]D24 +25.0 (c = 0.95, MeOH).
1H NMR (300 MHz, CDCl3): d = 2.40–2.46 (m, 2 H), 2.87–2.94 (m,
2 H), 3.83 (s, 3 H), 3.92 (s, 3 H), 4.08 (t, J = 7.0 Hz, 1 H), 4.35 (s, 2
H), 6.54 (s, 1 H), 7.10–7.15 (m, 2 H), 7.40–7.50 (m, 5 H), 7.76–7.79
(m, 2 H).
IR (KBr): 3418, 1746, 1616, 1441 cm–1.
1H NMR (300 MHz, D2O): d = 2.31–2.41 (m, 2 H), 2.89–2.98 (m, 2
H), 3.76 (s, 3 H), 4.18 (t, J = 6.6 Hz, 1 H), 6.75 (s, 1 H), 7.45–7.55
(m, 3 H), 7.69–7.71 (m, 2 H).
MS: m/z = 381 [M + 1].
MS: m/z = 260 [M + 1].
Anal. Calcd for C22H24N2O4·HCl (416.90): C, 63.38; H, 6.04; N,
6.72. Found: C, 63.27; H, 6.38; N, 6.57.
Anal. Calcd for C14H17N3O2·2HCl (332.23): C, 50.61; H, 5.76; N,
12.65. Found: C, 50.29; H, 5.70; N, 12.56.
(R)-(–)-2-Benzylamino-4-(5-phenyl-1H-pyrazol-3-yl)butyric
Acid Methyl Ester (13)
(S)-(+)-2-Amino-4-(1,5-diphenyl-1H-pyrazol-3-yl)butyric Acid
Methyl Ester (8b) (Method 2)
Isolated as a thick oil in 97% yield; [a]D24 –23.0 (c = 1, MeOH).
IR (CH2Cl2): 3414, 2922, 1742, 1618, 1510 cm–1.
Isolated as an off-white hydrochloride salt from compound 7c in
79% yield; mp 120–121 °C; [a]D24 +21.1 (c = 1, MeOH).
1H NMR (300 MHz, CDCl3): d = 1.93–2.12 (m, 2 H), 2.25 (s, 1 H),
2.79–2.84 (m, 2 H), 3.33–3.38 (m, 1 H), 3.64 (d, J = 14.0 Hz, 1 H),
3.71 (s, 3 H), 3.90 (d, J = 14.1 Hz, 1 H), 6.22 (s, 1 H), 6.90–6.93 (m,
3 H), 7.28–7.34 (m, 5 H), 7.61 (d, J = 15.0 Hz, 2 H), 12.70 (s, 1 H).
IR (KBr): 3434, 1720, 1629, 1456 cm–1.
1H NMR (300 MHz, D2O): d = 2.28–2.31 (m, 2 H), 2.74–2.86 (m, 2
H), 3.65 (s, 3 H), 4.18 (t, J = 6.6 Hz, 1 H), 6.34 (s, 1 H), 6.84–7.09
(m, 10 H).
MS: m/z = 350 [M + 1].
MS: m/z = 336 [M + 1].
Anal. Calcd for C21H23N3O2 (349.43): C, 72.18; H, 6.63; N, 12.03.
Found: C, 72.29; H, 6.70; N, 12.16.
Anal. Calcd for C20H21N3O2·2HCl (408.32): C, 58.83; H, 5.68; N,
10.29. Found: C, 58.77; H, 5.81; N, 9.99.
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2770
R. K. Singh et al.
PAPER
(S)-(+)-2-Amino-4-[5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-
3-yl]butyric Acid Methyl Ester (8c) (Method 2)
IR (KBr): 3426, 1630, 1587, 1485, 1407 cm–1.
1H NMR (300 MHz, TFA-d): d = 2.72–2.78 (m, 2 H), 3.33–3.43 (m,
2 H), 4.57 (br s, 1 H), 6.93 (s, 1 H), 7.26–7.29 (m, 2 H), 7.34–7.39
(m, 4 H), 7.45–7.65 (m, 4 H).
Isolated as an off-white hydrochloride salt from compound 7d in
82% yield; mp 133–134 °C; [a]D24 +20.9 (c = 0.098, MeOH).
IR (KBr): 3423, 2933, 1743, 1613, 1508, 1438 cm–1.
MS: m/z = 322 [M + 1].
1H NMR (300 MHz, D2O): d = 2.26–2.30 (m, 2 H), 2.72–2.80 (m, 2
H), 3.36 (s, 3 H), 3.70 (s, 3 H), 4.21 (t, J = 6.5 Hz, 1 H), 6.28 (s, 1
H), 6.43–7.05 (m, 9 H).
Anal. Calcd for C19H19N3O2 (321.37): C, 71.01; H, 5.96; N, 13.08.
Found: C, 70.87; H, 6.11; N, 13.25.
MS: m/z = 366 [M + 1].
(S)-(+)-2-Amino-4-[5-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-
3-yl]butyric Acid (9c)
Anal. Calcd for C21H23N3O3·2HCl (438.35): C, 57.54; H, 5.75; N,
9.59. Found: C, 57.29; H, 5.66; N, 9.42.
Isolated as a white solid in 90% yield; mp 190–191 °C; [a]D24 +11.5
(c = 1, MeOH); HPLC purity: 99.5%, and chiral purity: 98.1%.
(S)-(+)-2-Amino-4-[1,5-bis-(4-methoxyphenyl)-1H-pyrazol-3-
yl)butyric Acid Methyl Ester (8d) (Method 2)
IR (KBr): 3562, 1646, 1504, 1250 cm–1.
1H NMR (300 MHz, TFA-d): d = 2.90–2.96 (m, 2 H), 3.50–3.55 (m,
2 H), 4.03 (s, 3 H), 4.55 (s, 1 H), 7.08–7.15 (m, 3 H), 7.40–7.45 (m,
4 H), 7.70–7.78 (m, 3 H).
Isolated as a white hydrochloride salt from compound 7e in 93%
yield; mp 128–129 °C; [a]D24 +33.9 (c = 1.5, MeOH).
IR (KBr): 3440, 1743, 1710, 1617, 1520, 1240 cm–1.
MS: m/z = 352 [M + 1].
1H NMR (300 MHz, D2O): d = 2.23–2.34 (m, 2 H), 2.71–2.85 (m, 2
H), 3.32 (s, 3 H), 3.46 (s, 3 H), 3.67 (s, 3 H), 4.18 (t, J = 6.5 Hz, 1
H), 6.29 (s, 1 H), 6.41–6.44 (m, 2 H), 6.59–6.62 (m, 2 H), 6.68–6.92
(m, 4 H).
Anal. Calcd for C20H21N3O3 (351.40): C, 68.36; H, 6.02; N, 11.96.
Found: C, 68.55; H, 6.01; N, 12.10.
(S)-(+)-2-Amino-4-[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-
MS: m/z = 396 [M + 1].
yl]butyric Acid (9d)
Isolated as an off-white solid in 97% yield; mp 118–119 °C; [a]D
+19.9 (c = 1.6, MeOH); HPLC purity: 99.3%, and chiral purity:
24
Anal. Calcd for C22H25N3O4·2HCl (468.37): C, 56.42; H, 5.81; N,
8.97. Found: C, 56.67; H, 5.83; N, 9.03.
98.5%.
(R)-(–)-2-Amino-4-(5-phenyl-1H-pyrazol-3-yl)butyric Acid
Methyl Ester (14) (Method 1)
IR (KBr): 3429, 1639, 1590, 1489, 1408 cm–1.
1H NMR (300 MHz, TFA-d): d = 2.05–2.10 (m, 2 H), 2.64–2.66 (m,
2 H), 3.19 (s, 3 H), 3.31 (s, 3 H), 3.93 (br s, 1 H), 6.11 (s, 1 H), 6.24–
6.26 (m, 4 H), 6.70–6.73 (m, 4 H).
Isolated as a white hydrochloride salt from compound 13 in 83%
yield; mp 160–161 °C; [a]D24 –22.7 (c = 0.90, MeOH).
IR (KBr): 3491, 2920, 1741, 1628, 1489 cm–1.
MS: m/z = 382 [M + 1].
1H NMR (300 MHz, D2O): d = 2.29–2.36 (m, 2 H), 2.80–2.86 (m, 2
H), 3.70 (s, 3 H), 4.14 (t, J = 6.6 Hz, 1 H), 6.60 (s, 1 H), 7.39–7.46
(m, 3 H), 7.67–7.69 (m, 2 H).
Anal. Calcd for C21H23N3O4 (381.43): C, 66.13; H, 6.08; N, 11.02.
Found: C, 65.89; H, 5.86; N, 11.27.
MS: m/z = 260 [M + 1].
(R)-(–)-2-Amino-4-(5-phenyl-1H-pyrazol-3-yl)butyric Acid (15)
Isolated as a white solid in 90% yield; mp 234–235 °C; [a]D24 –32.9
(c = 1.2, MeOH); HPLC purity: 99.3%, and chiral purity: 98.9%.
IR (KBr): 3423, 1643, 1599, 1470, 1410 cm–1.
Anal. Calcd for C14H17N3O2·2HCl (332.23): C, 50.61; H, 5.76; N,
12.65. Found: C, 50.78; H, 5.91; N, 12.63.
Ester Hydrolysis of 8 and 14; General Method
1H NMR (300 MHz, TFA-d): d = 2.65–2.70 (m, 2 H), 3.35–3.40 (m,
A solution of amino acid esters 8 or 14 (1.0 g) in 6 N HCl (5 mL)
was refluxed under stirring for 4–6 h and then evaporated. The res-
idue was suspended in CHCl3, and a 4 N CHCl3–NH3 solution was
added at 0 °C until the pH was neutral and the resulting reaction
mixture was stirred at the same temperature for 10 min. The solid,
which separated out, was filtered, washed with water and dried to
afford the pure amino acid.
2 H), 4.58 (s, 1 H), 6.98 (s, 1 H), 7.60–7.78 (m, 5 H).
MS: m/z = 246 [M + 1].
Anal. Calcd for C13H15N3O2 (245.28): C, 63.66; H, 6.16; N, 17.13.
Found: C, 63.39; H, 6.10; N, 16.99.
Acknowledgment
(S)-(+)-2-Amino-4-(5-phenyl-1H-pyrazol-3-yl)butyric Acid (9a)
Isolated as an off-white solid in 88% yield; mp 240–241 °C; [a]D
+34.8 (c = 1.6, MeOH); HPLC purity: 98.9%, and chiral purity:
We thank CSIR New Delhi, for Research Fellowship to RKS and fi-
nancial support for this work. We are also grateful to Analytical
Chemistry Division for IR, 1H NMR, mass spectroscopy, elemental
analyses, optical rotation and chiral HPLC analyses of the com-
pounds synthesized.
24
99.1%.
IR (KBr): 3426, 1636, 1593, 1494, 1410 cm–1.
1H NMR (300 MHz, TFA-d): d = 2.70–2.80 (m, 2 H), 3.35–3.40 (m,
2 H), 4.59 (br s, 1 H), 6.95 (s, 1 H), 7.59–7.73 (m, 5 H).
References
MS: m/z = 246 [M + 1].
(1) Current address: Medicinal Chemistry Division, New
Chemical Entity Research, Lupin Research Park, 46/47A,
Village Nande, Taluka Mulshi, Pune 411 042, India.
(2) (a) Srinivasan, G.; James, C. M.; Krzycki, J. A. Science
2002, 296, 1459. (b) Hao, B.; Gong, W.; Ferguson, T. K.;
James, C. M.; Krzycki, J. A.; Chan, M. K. Science 2002,
296, 1462. (c) Lindley, M. Nature (London) 1977, 266, 776.
Anal. Calcd for C13H15N3O2·0.8H2O (259.696): C, 60.12; H, 6.44;
N, 16.18. Found: C, 59.96; H, 6.70; N, 15.91.
(S)-(+)-2-Amino-4-(1,5-diphenyl-1H-pyrazol-3-yl)butyric Acid
(9b)
Isolated as a white solid in 96% yield; [a]D24 +4.1 (c = 1.6, MeOH);
mp 215–216 °C; HPLC purity: 98.1%, and chiral purity: 98.7%.
Synthesis 2005, No. 16, 2765–2771 © Thieme Stuttgart · New York

PAPER
Synthesis of (2S)-/(2R)-2-Amino-4-(1-aryl-/1,5-diaryl-1H-pyrazol-3-yl)butyric Acid
2771
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Synthesis 2005, No. 16, 2765–2771 © Thieme Stuttgart · New York