Synthesis of pyrazole containing α-amino acids via a highly regioselective condensation/aza-Michael reaction of β-aryl α,β-unsaturated ketones

Article abstract of DOI:10.1039/c5ob00364d

A synthetic approach for the preparation of a new class of highly conjugated unnatural α-amino acids bearing a 5-arylpyrazole side-chain has been developed. Horner-Wadsworth-Emmons reaction of an aspartic acid derived β-keto phosphonate ester with a range of aromatic aldehydes gave β-aryl α,β-unsaturated ketones. Treatment of these with phenyl hydrazine followed by oxidation allowed the regioselective synthesis of pyrazole derived α-amino acids. As well as evaluating the fluorescent properties of the α-amino acids, their synthetic utility was also explored with the preparation of a sulfonyl fluoride derivative, a potential probe for serine proteases.

Full text of DOI:10.1039/c5ob00364d

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DOI: 10.1039/C5OB00364D
ARTICLE
Synthesis of pyrazole containing α-amino acids via a
highly regioselective condensation/aza-Michael
reaction of β-aryl α,β-unsaturated ketones
Cite this: DOI: 10.1039/x0xx00000x
Lynne Gilfillan,a Raik Artschwager,a Alexander H. Harkiss,a Rob M. J. Liskampa,b
and Andrew Sutherland*a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
A synthetic approach for the preparation of a new class of highly conjugated unnatural α-
amino acids bearing a 5-arylpyrazole side-chain has been developed. Horner-Wadsworth-
Emmons reaction of an aspartic acid derived β-keto phosphonate ester with a range of
aromatic aldehydes gave β-aryl α,β-unsaturated ketones. Treatment of these with phenyl
hydrazine followed by oxidation allowed the regioselective synthesis of pyrazole derived α-
amino acids. As well as evaluating the fluorescent properties of the α-amino acids, their
synthetic utility was also explored with the preparation of a sulfonyl fluoride derivative, a
potential probe for serine proteases.
www.rsc.org/
interesting properties and applications, flexible and general
synthetic routes for the preparation of optically active pyrazole
Introduction
containing α-amino acids are still relatively limited.5b,7,9–11
Noteworthy approaches include the cyclocondensation of α-
hydrazinoamino acids with 3-trimethylsilanylpropynones or
enamino ketones.9 More recently, Conti and co-workers
With continued advances in chemical biology and biomedical
and life sciences, non-proteinogenic α-amino acids are being
increasingly used as probes to study the mechanism of
biological processes, investigate the bioactive conformations of
proteins and facilitate the discovery of new pharmacologically
active compounds.1,2 Furthermore, in the field of organic
synthesis, many unnatural α-amino acids have been used as
chiral building blocks, ligands and catalysts.3 Due to this
increasing range of applications, novel classes of non-
proteinogenic α-amino acids and methods for their synthesis
are still very much in demand.2,3
prepared 3-carboxypyrazole derivatives via
a 1,3-dipolar
cycloaddition of allylglycine with hydrazine derived
nitrilimines,7 while Wei and Lubell used the nucleophilic ring-
opening of serine derived cyclic sulfamidates for the
preparation of β-diketone α-amino acids which were then
converted to the corresponding pyrazole by condensation with
hydrazine.10a
In recent years, there has been much interest in developing
the synthesis and applications of unnatural α-amino acids with
heteroaryl containing side-chains.2,4 For example, following the
isolation and discovery of a naturally occurring pyrazole
containing α-amino acid, (S)-β-pyrazolylalanine (1) (Fig. 1)
from Citrullus vulgaris,5 various biological applications of
novel pyrazole containing α-amino acids have been reported.
Pyrazole analogues of ibotenic acid were shown to be selective
CO2H
NH2
CO2H
NH2
N
HO2C
NPh
N
N
1
2
N
HO2C
H2N
N
CO2Me
antagonists of the metabotropic glutamate receptor
(mGluR2),6 while a number of 3-carboxypyrazole α-amino
acids (e.g. 2) are antagonists of the N-methyl- -aspartic acid
2
D
3
(NMDA) receptor.7 The antitumor activity of ferrocenyl
derived α-amino acids linked via a pyrazole moiety has also
been demonstrated.8 Other applications include using the
rigidity of the pyrazole moiety to generate conformationally
restricted peptidomimetics such as α-amino acid 3, which
mimics the cis-amide bond.9 Despite exhibiting a range of
Fig. 1 Biologically active pyrazole containing α-amino acids.
Recently, we reported an efficient approach for the
preparation of a rare class of α-amino acid with enone side
chains.12 In exploring the reactivity and application of these
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amino acids, we discovered that these could undergo selective (36–72 h). While other methods have recently been reported for
6-endo-trig cyclisations for the synthesis of 4-oxopipecolic the preparation of these types of enone derived α-amino acids,15
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acids,13 and had potential as biological probes with the the approach described in Scheme 2 is particularly robust,
DOI: 10.1039/C5OB00364D
preparation of a highly fluorescent 4-dimethylamino-1-naphthyl allowing the mutli-gram synthesis of these compounds in
enone analogue.12 Despite these advances, we found that on excellent overall yields from
long-term storage, the enones were prone to decomposition. In
L-aspartic acid.
an effort to further explore the reactivity of these compounds
1. SOCl2, MeOH,
Δ, 3 h, 100%
and produce more robust biologically functional probes, we
proposed to investigate heterocyclisation reactions of the enone
derived α-amino acids. We now report the development of a
highly regioselective condensation/aza-Michael reaction as the
key step for the preparation of a new class of α-amino acids
bearing 5-arylpyrazole side-chains (Scheme 1). As well as
exploring selective deprotection strategies to the parent α-
amino acids and measuring their fluorescent properties, the
application of one of these compounds for the preparation of a
sulfonyl fluoride, well-established serine protease inhibitors is
also described.
CO2H
CO2Me
HO2C
MeO2C
2. TrCl, Et3N,
CH2Cl2, rt, 24 h,
100%
NH2
NHTr
5
4
(MeO)2POMe,
n-BuLi, THF,
−78 °C, 2 h, 92%
RCHO, K2CO3,
MeCN
MeO
MeO
R
CO2Me
NHTr
CO2Me
NHTr
P
50 °C,
24−72 h
O
O
O
7 R= Ph, 95%
6
8 R= 4-NO2C6H4, 72%
9 R= 4-MeOC6H4, 76%
10 R= 2-Naphthyl, 89%
11 R= 4-(3'-NO2C6H4)C6H4, 84%
Scheme 2 Synthesis of β-aryl E-enones.
CO2H
NH2
R
N
N
Methods for formation of the pyrazoles via 2-pyrazolines by
reaction of enones 7–11 with phenyl hydrazine were next
investigated. Under neutral or acidic conditions, 2-pyrazolines
can be prepared by the reaction of enones and hydrazines
through a two-stage process involving imine condensation to
form a hydrazone, followed by an aza-Michael reaction to
complete the cyclisation.16 Initially, reaction of 7 with phenyl
hydrazine was attempted under neutral conditions. However,
analysis by 1H NMR spectroscopy showed that the reaction had
not gone to completion forming only the hydrazone
intermediate. As more forcing, acidic conditions were
necessary, the acid-labile N-trityl protected α-amino acids 7–11
were converted to the N-Cbz derivatives (Scheme 3). Amino
acids 7–11 were easily deprotected using TFA under mild
conditions. Without purification, the resulting amines were
treated with benzyl chloroformate in the presence of Hünig’s
base, which gave the Cbz-derivatives 12–16 in high yields over
the two-steps (77–87%). Reaction of N-Cbz protected enone 12
with phenyl hydrazine in the presence of HCl was then
investigated. Under reflux conditions, this produced the
corresponding 2-pyrazoline cleanly, as a single regiosiomer.
While not important for the synthesis of pyrazoles, it was noted
using NMR spectroscopy that the aza-Michael step proceeded
without any asymmetric bias from the chiral α-position,
forming a 1:1 mixture of diastereomers. Without purification,
the 2-pyrazoline was oxidised using DDQ under mild
conditions and this gave pyrazole 17 in 76% yield over the two-
steps.17 With an optimised approach in hand, the scope of this
process was then explored using the other enones with electron-
rich, electron-deficient and highly conjugated side-chains. With
all the examples, the corresponding pyrazoles were formed as a
single regioisomer in high yields (73–84%).
Ph
CO2Me
NHCbz
R
R
CO2Me
1. PhNHNH2
2. Oxidation
N
N
O
NHCbz
Ph
R= aryl group
R
SO2F
NHCbz
N
N
Ph
Scheme 1 Proposed approach to novel 5-arylpyrazole α-amino acid derivatives.
Results and discussion
The project began with the preparation of a series of enone
derived α-amino acids (Scheme 2).12,13 Reaction of
L
-aspartic
acid (4) with thionyl chloride in methanol followed by N-trityl
protection under basic conditions gave N-trityl
L-aspartate
dimethyl ester 5 in quantitative yield.14 Using the N-trityl group
to block the α-methyl ester allowed the highly regioselective
reaction of
5
with the lithium anion of dimethyl
methylphosphonate. This gave β-ketophosphonate ester 6 as the
sole product in 92% yield. To generate stable, highly
conjugated heterocycle derived α-amino acids with the
potential to act as fluorescent probes, enones with β-aryl side
chains were prepared. Under mild conditions, Horner-
Wadsworth-Emmons reaction of 6 with various aryl aldehydes
gave the corresponding β-aryl E-enones 7–11 in high yields
(72–95%). As expected, the reactions of the electron deficient
aldehydes were complete after 24 h, while the electron rich and
more conjugated analogues required extended reaction times
2 | J. Name., 2012, 00, 1-3
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CO2Me
Cs2CO3,
MeOH, H2O
CO2H
R
R
1. TFA, CH2Cl2,
rt, 2 h
View Article Online
NHCbz
DOI: 10.1039/C5OB00364D
R
CO2Me
R
CO2Me
N
NHCbz
17−21
N
N
N
rt, 16 h
2. BnOCOCl,
DIPEA, CH2Cl2,
rt, 1 h
O
NHTr
7−11
O
NHCbz
Ph
Ph
12 R= Ph, 86%
13 R= 4-NO2C6H4, 77%
14 R= 4-MeOC6H4, 87%
15 R= 2-Naphthyl, 85%
6 M HCl,
Δ, 48 h
6 M HCl,
Δ, 24 h
16 R= 4-(3'-NO2C6H4)C6H4, 84%
CO2H
CO2H
R
R
PhNHNH2, MeOH,
HCl, Δ, 17 h
N
N
N
NH2.HCl
NH2.HCl
N
Ph
25 R= 4-NO2C6H4, 97%
26 R= 4-(3'-NO2C6H4)C6H4, 98%
Ph
CO2Me
NHCbz
17−21
DDQ, CH2Cl2,
rt, 2 h
CO2Me
NHCbz
R
R
22 R= Ph, 88%
23 R= 4-MeOC6H4, 79%
24 R= 2-Naphthyl, 83%
N
N
N
N
Ph
Ph
Scheme 4 Deprotection strategies for preparation of α-amino acids 22–26.
O2N
CO2Me
NHCbz
CO2Me
NHCbz
The specific use of aryl substituents for the pyrazoles was to
generate α-amino acids with highly conjugated side-chains that
would possess fluorescent properties.18 Therefore, following the
synthesis of compounds 22–26, the absorption and fluorescence
spectra were recorded (Table 1). The absorption and emission
maxima showed some correlation with the electronic nature of
the aryl substituents. For example, the electron deficient groups
generally absorbed and emitted at longer wavelengths. While
compounds 22–26 all showed some degree of fluorescence, the
naphthyl and 4-nitrophenyl analogues 24 and 25, in particular
showed strong fluorescence with maxima at 356 and 415 nm,
respectively (Fig. 2).
N
N
N
N
Ph
Ph
18, 76%
17, 76%
MeO
CO2Me
NHCbz
CO2Me
NHCbz
N
N
N
N
Ph
19, 75%
Ph
20, 73%
CO2Me
NHCbz
O2N
N
N
Ph
21, 84%
Scheme 3 Synthesis of pyrazole derived α-amino acids 17–21.
Table 1 Absorbance and emission data for compounds 22–26a
Compound
λAbs (nm)
250
λEm (nm)
367
ε (cm–1M–1)
13320
22
23
24
25
26
254
249
303
270
348
356
415
434
6170
23650
10060
26940
To access the parent α-amino acids, various strategies were
explored. We wanted to demonstrate that the α-carboxylic acid
position could be selectively deprotected under mild conditions
to give N-Cbz protected α-amino acids that could have direct
application in peptide synthesis. Using compounds 17, 19 and
20, hydrolysis of the ester moiety with cesium carbonate at
room temperature gave the N-Cbz protected α-amino acids
cleanly. Without purification, removal of the amino protecting
group under acidic conditions then gave α-amino acids 22–24
in 79–88% yields over the two steps. Using the nitro-substituted
α-amino acids, a one-step procedure was also developed. Acid
mediated deprotection of compounds 18 and 21 using 6 M HCl
resulted in the removal of both protecting groups, allowing the
isolation of α-amino acids 25 and 26 in essentially quantitative
yields. Overall, this approach for the preparation of α-amino
acids bearing 5-arylpyrazole side-chains was general and
efficient, allowing the synthesis of the target α-amino acids in
a The spectra were recorded in methanol at a concentration of 1 × 10–5 M.
800
700
Naphthyl 24
4-Nitrophenyl 25
600
500
400
300
200
100
0
315
335
355
375
395
415
435
455
475
36–53% overall yield from L-aspartic acid.
wavelength (nm)
Fig. 2 Emission spectra for α-amino acids 24 and 25.
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MsCl, Et N,
CH2Cl2
O2N
O2N
O2N
3
NaBH4, LiCl,
THF, EtOH
CO2Me
NHCbz
OH
NHCbz
ViewOAMrtsicle Online
DOI: 10.1039/C5OB00364D
N
N
0 °C to rt,
0.5 h, 92%
rt, 7 h,
95%
N
NHCbz
N
N
N
Ph
Ph
Ph
18
27
28
AcSH, Cs2CO3,
DMF, rt,
16 h, 85%
1. 30% H2O2,AcOH,
NaOAc, rt,
O2N
O2N
16 h, 100%
SO2F
NHCbz
SAc
NHCbz
N
N
2. 3HF.NEt3,
N
N
CH2Cl2, Δ, 20 h, 64%
Ph
Ph
31
−BF4 F
29
O
N
S
F
30
Scheme 5 Synthesis of sulfonyl fluoride 31.
Conclusions
The emission maxima for the naturally occurring α-amino
acid, tryptophan occurs at similar wavelength (λEm = 352 nm)
to naphthyl analogue 24.19 This would obviously limit
applications of 24 when incorporated into proteins and peptides
containing tryptophan. So despite showing weaker
fluorescence, it was decided to investigate applications of 4-
nitrophenyl analogue 25, which has an emission maximum at
higher wavelength compared to proteinogenic α-amino acids.20
Sulfonyl fluorides derived from α-amino acids and peptides
have been synthesised and shown to act as electrophilc traps for
the potent inhibition of protease enzymes.21,22 In particular, a N-
Cbz protected tetrapeptide incorporating a sulfonyl fluoride unit
has demonstrated broad-spectrum antimalarial activity.23 In this
project, we wished to investigate whether a sulfonyl fluoride
unit could be incorporated into 5-(4’-nitrophenyl)pyrazole α-
amino acid 18. The product of this process would generate a
multi-functional compound that would have potential as both a
protease inhibitor and could undergo further transformations
such as peptide synthesis for development as a biological probe.
The ester moiety of 18 was initially reduced under mild
conditions using sodium borohydride and lithium chloride
(Scheme 5). This gave alcohol 27 in 95% yield. The hydroxyl
group was activated as the mesylate under standard conditions,
and this was then displaced by in situ generated cesium
thioacetate forming 29 in high yield. Oxidation of thioacetate
29 with aqueous hydrogen peroxide in the presence of sodium
acetate gave the corresponding sodium sulfonate salt in
quantitative yield. Sodium sulfonates can be converted to
sulfonyl fluorides by treatment with oxalyl chloride and then
reaction of the resulting sulfonyl chloride with potassium
fluoride, or directly using DAST.21,22a For the preparation of
sulfonyl fluoride 31, it was found that direct reaction of the
sodium sulfonate salt with triethylamine trihydrofluoride and
XtalFluor-M® 30 gave the target compound very cleanly, in
64% yield. The synthesis of sulfonyl fluoride 31 in 48% overall
yield from 18 demonstrates the synthetic utility of pyrazole
derived α-amino acids and their use for the synthesis of
potential functionalised biological probes.
In summary, a series of novel pyrazole derived α-amino acids
have been prepared from -aspartic acid using highly
L
regioselective transformations such as a Horner-Wadsworth-
Emmons reaction and a one-pot condensation/aza-Michael
process. The synthetic utility of these compounds was explored
with the efficient transformation of 5-(4’-nitrophenyl)pyrazole
α-amino acid 18 to sulfonyl fluoride derivative 31, a potential
serine protease inhibitor. The absorption and emission
properties of the pyrazole derived α-amino acids were also
recorded with compounds 24 and 25 showing particularly
strong fluorescence. This part of the study has revealed the
structural features and level of conjugation required for the
generation of heterocyclic derived α-amino acids with
appropriate emission maxima for application as fluorescent
probes. Using this information, the development of new
heterocyclisation reactions of enone derived α-amino acids are
currently underway. Exploration of the use of sulfonyl fluorides
such as 31 as components of peptide-based inhibitors is also
being studied. The results of these investigations will be
reported in due course.
Experimental
Reactions were performed in flame-dried glassware under a
positive atmosphere of argon. All reagents and starting
materials were obtained from commercial sources and used as
received. Dry solvents were purified using a PureSolv 500 MD
solvent purification system. Flash column chromatography was
carried out using Fisher matrix silica 60. Macherey–Nagel
aluminium-backed plates pre-coated with silica gel 60 (UV254
were used for thin layer chromatography and were visualised
by staining with KMnO4. H NMR and 13C NMR spectra were
recorded on a Bruker DPX 400 spectrometer or Bruker 500
spectrometer with chemical shift values in ppm relative to TMS
(δH 0.00 and δC 0.0) or residual chloroform (δH 7.28 and δC
77.2) as standard. Assignment of H and 13C NMR signals are
)
1
1
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based on two-dimensional COSY and DEPT experiments, H); δC (101 MHz, CDCl3) 43.0 (CH2), 50.2 (CH), 53.0 (CH3),
respectively. Mass spectra were obtained using a JEOL JMS- 67.3 (CH2), 124.4 (2 × CH), 128.2 (2 × CH), 128.4 (CH), 128.7
View Article Online
700 spectrometer. Infrared spectra were recorded using Golden (2 × CH), 128.9 (CH), 129.1 (2 × CH), 136.3 (C), 140.4 (C),
DOI: 10.1039/C5OB00364D
Gate apparatus on a JASCO FTIR 410. Melting points were 140.9 (CH), 149.0 (C), 156.2 (C), 171.5 (C), 197.0 (C); m/z
determined on a Reichert platform melting point apparatus. (CI) 413.1352 (MH+. C21H21N2O7 requires 413.1349), 383
Optical rotations were determined as solutions irradiating with (42%), 348 (38), 305 (30), 275 (30), 257 (23), 137 (68), 91
the sodium D line (λ = 589 nm) using an Auto pol V (68), 69 (100).
polarimeter. [α]D values are given in units 10–1 deg cm2 g–1.
Methyl (2S,5E)-2-[(benzyloxycarbonyl)amino]-4-oxo-6- methoxyphenyl)-4-oxohex-5-enoate (14). The reactions were
Methyl
(2S,5E)-2-[(benzyloxycarbonyl)amino]-6-(4’-
phenylhex-5-enoate (12). To a solution of methyl (2S,5E)-4- performed as described for 7 using methyl (2S,5E)-6-(4’-
oxo-6-phenyl-2-(tritylamino)hex-5-enoate (7) (1.06 g, 2.23 methoxyphenyl)-4-oxo-2-(tritylamino)hex-5-enoate (9) (0.60 g,
mmol) in dichloromethane (45 mL) was added trifluoroacetic 1.19
mmol).
This
gave
methyl
(2S,5E)-2-
acid (0.33 mL, 4.50 mmol). The reaction mixture was stirred at [(benzyloxycarbonyl)amino]-6-(4’-methoxyphenyl)-4-oxohex-
room temperature for 2 h before concentrating in vacuo. The 5-enoate (14) as a colourless oil (0.41 g, 87%). νmax/cm−1 (neat)
resulting residue was dissolved in chloroform (5 mL) and 3347 (NH), 2953 (CH), 1717 (C=O), 1655 (C=O), 1597 (C=C),
29
petroleum ether was added until an orange oil formed. The 1510 (C=C), 1248, 1208, 1169, 1026, 816; [α]D +30.3 (c 1.0,
solvent was then decanted off, and the remaining oil was CHCl3); δH (400 MHz, CDCl3) 3.23 (1H, dd, J 17.9, 4.2 Hz, 3-
dissolved in dichloromethane (30 mL) followed by the addition HH), 3.47 (1H, dd, J 17.9, 4.2 Hz, 3-HH), 3.75 (3H, s, OCH3),
of N,N-diisopropylethylamine (0.97 mL, 5.58 mmol) and 3.85 (3H, s, OCH3), 4.67 (1H, dt, J 8.5, 4.2 Hz, 2-H), 5.12 (2H,
benzyl chloroformate (0.48 mL, 3.35 mmol). The reaction s, OCH2Ph), 5.88 (1H, d, J 8.5 Hz, NH), 6.58 (1H, d, J 16.2 Hz,
mixture was stirred at room temperature for 1 h before diluting 5-H), 6.92 (2H, d, J 8.8 Hz, 3’-H and 5’-H), 7.27−7.38 (5H, m,
with water (50 mL). The mixture was then extracted with Ph), 7.49 (2H, d, J 8.8 Hz, 2’-H and 6’-H), 7.52 (1H, d, J 16.2
dichloromethane (4 × 50 mL), dried (MgSO4) and concentrated Hz, 6-H); δC (101 MHz, CDCl3) 42.3 (CH2), 50.3 (CH), 52.8
in vacuo. The resulting residue was purified by column (CH3), 55.6 (CH3), 67.1 (CH2), 114.6 (2 × CH), 123.4 (CH),
chromatography (elution with 50% ethyl acetate in petroleum 126.9 (C), 128.1 (2 × CH), 128.2 (CH), 128.6 (2 × CH), 130.4
ether) to give methyl (2S,5E)-2-[(benzyloxycarbonyl)amino]-4- (2 × CH), 136.4 (C), 144.0 (CH), 156.2 (C), 162.1 (C), 171.8
oxo-6-phenylhex-5-enoate (12) as a white solid (0.70 g, 86%). (C), 197.4 (C); m/z (EI) 397.1526 (M+. C22H23NO6 requires
Mp 77−78 °C; νmax/cm−1 (neat) 3333 (NH), 3059, 2951 (CH), 397.1525), 336 (10%), 289 (19), 262 (19), 243 (45), 182 (34),
1734 (C=O), 1688 (C=O), 1533 (C=C), 1435, 1343, 1254, 161 (100), 91 (32).
26
1090, 980, 748; [α]D +26.5 (c 1.0, CHCl3); δH (400 MHz, Methyl
(2S,5E)-2-[(benzyloxycarbonyl)amino]-6-
CDCl3) 3.26 (1H, dd, J 17.9, 4.2 Hz, 3-HH), 3.48 (1H, dd, J (naphthalen-2’-yl)-4-oxohex-5-enoate (15). The reactions
17.9, 4.2 Hz, 3-HH), 3.75 (3H, s, OCH3), 4.68 (1H, dt, J 8.4, were performed as described for 7 using methyl (2S,5E)-6-
4.2 Hz, 2-H), 5.12 (2H, s, OCH2Ph), 5.85 (1H, d, J 8.4 Hz, (naphthalen-2’-yl)-4-oxo-2-(tritylamino)hex-5-enoate
(10)
NH), 6.69 (1H, d, J 16.2 Hz, 5-H), 7.26−7.43 (8H, m, ArH), (0.56 g, 1.07 mmol). This gave methyl (2S,5E)-2-
7.51−7.59 (3H, m, 6-H and ArH); δC (101 MHz, CDCl3) 42.4 [(benzyloxycarbonyl)amino]-6-(naphthalen-2’-yl)-4-oxohex-5-
(CH2), 50.2 (CH), 52.9 (CH3) 67.2 (CH2), 125.6 (CH), 128.2 (2 enoate (15) as a colourless oil (0.38 g, 85%). νmax/cm−1 (neat)
× CH), 128.3 (CH), 128.6 (4 × CH), 129.2 (2 × CH), 131.0 3339 (NH), 2951 (CH), 1717 (C=O), 1659 (C=O), 1505 (C=C),
28
(CH), 134.2 (C), 136.4 (C), 144.2 (CH), 156.2 (C), 171.7 (C), 1207, 1057, 976, 812; [α]D +27.5 (c 1.0, CHCl3); δH (400
197.6 (C); m/z (CI) 368.1506 (MH+. C21H22NO5 requires MHz, CDCl3) 3.31 (1H, dd, J 18.0, 4.2 Hz, 3-HH), 3.54 (1H,
368.1498), 326 (8%), 260 (23), 234 (21), 219 (18), 181 (6), 147 dd, J 18.0, 4.2 Hz, 3-HH), 3.77 (3H, s, OCH3), 4.71 (1H, dt, J
(17), 107 (16), 85 (100).
8.6, 4.2 Hz, 2-H), 5.13 (2H, s, OCH2Ph), 5.89 (1H, d, J 8.6 Hz,
Methyl (2S,5E)-2-[(benzyloxycarbonyl)amino]-6-(4’- NH), 6.82 (1H, d, J 16.2 Hz, 5-H), 7.28−7.39 (5H, m, Ph),
nitrophenyl)-4-oxohex-5-enoate (13). The reactions were 7.51−7.58 (2H, m, 6’-H and 7’-H), 7.67 (1H, dd, J 8.6, 1.5 Hz,
performed as described for 7 using methyl (2S,5E)-6-(4’- 3’-H), 7.73 (1H, d, J 16.2 Hz, 6-H), 7.82−7.90 (3H, m, 4’-H,
nitrophenyl)-4-oxo-2-(tritylamino)hex-5-enoate (8) (0.39 g, 5’-H and 8’-H), 7.96 (1H, br s, 1’-H); δC (101 MHz, CDCl3)
0.75
mmol).
This
gave
methyl
(2S,5E)-2- 42.5 (CH2), 50.2 (CH), 52.9 (CH3), 67.2 (CH2), 123.6 (CH),
125.7 (CH), 127.0 (CH), 127.7 (CH), 127.9 (CH), 128.1 (2 ×
[(benzyloxycarbonyl)amino]-6-(4’-nitrophenyl)-4-oxohex-5-
enoate (13) as a yellow solid (0.24 g, 77%). Mp 73−74 °C; CH), 128.3 (CH), 128.6 (2 × CH), 128.8 (CH), 129.0 (CH),
νmax/cm−1 (neat) 3331 (NH), 2953 (CH), 1730 (C=O), 1686 130.9 (CH), 131.7 (C), 133.4 (C), 134.6 (C), 136.4 (C), 144.3
28
(C=O), 1512 (C=C), 1343, 1202, 1059, 978, 860; [α]D +20.6 (CH), 156.2 (C), 171.7 (C), 197.5 (C); m/z (CI) 418.1653
(c 1.0, CHCl3); δH (400 MHz, CDCl3) 3.30 (1H, dd, J 18.1, 4.2 (MH+. C25H24NO5 requires 418.1654), 383 (32%), 310 (48),
Hz, 3-HH), 3.48 (1H, dd, J 18.1, 4.2 Hz, 3-HH), 3.76 (3H, s, 275 (20), 147 (30), 107 (29).
OCH3), 4.70 (1H, dt, J 8.4, 4.2 Hz, 2-H), 5.12 (2H, s, OCH2Ph), Methyl
(2S,5E)-2-[(benzyloxycarbonyl)amino]-6-(3”-
5.82 (1H, d, J 8.4 Hz, NH), 6.80 (1H, d, J 16.2 Hz, 5-H), nitrobiphen-4’-yl)-4-oxohex-5-enoate (16). The reactions
7.29−7.37 (5H, m, Ph), 7.58 (1H, d, J 16.2 Hz, 6-H), 7.69 (2H, were performed as described for 7 using methyl (2S,5E)-6-(3”-
d, J 8.8 Hz, 2’-H and 6’-H), 8.26 (2H, d, J 8.8 Hz, 3’-H and 5’- nitrobiphen-4’-yl)-4-oxo-2-(tritylamino)hex-5-enoate (11) (0.55
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

Organic & Biomolecular Chemistry
Page 6 of 10
Journal Name
ARTICLE
g, 0.92
mmol).
This
gave
methyl
(2S,5E)-2- Methyl
(2S)-2-[(benzyloxycarbonyl)amino]-3-[5’-(4”-
[(benzyloxycarbonyl)amino]-6-(3”-nitrobiphen-4’-yl)-4-
nitrophenyl)-1’-phenyl-1’H-pyrazol-3’-yl]propanoate (18).
oxohex-5-enoate (16) as a pale yellow solid (0.38 g, 84%). Mp The reactions were carried out as described for 12VuieswinAgrticmle eOtnhliynel
DOI: 10.1039/C5OB00364D
102−104 °C; νmax/cm−1 (neat) 3325 (NH), 2953 (CH), 1742 (2S,5E)-2-[(benzyloxycarbonyl)amino]-6-(4’-nitrophenyl)-4-
(C=O), 1683 (C=O), 1664 (C=O), 1529 (C=C), 1342, 1179, oxohex-5-enoate (13) (0.15 g, 0.36 mmol). Purification by
27
1057, 970, 802; [α]D +17.2 (c 1.0, CHCl3); δH (400 MHz, column chromatography (elution with 20–40% ethyl acetate in
CDCl3) 3.29 (1H, dd, J 18.0, 4.2 Hz, 3-HH), 3.51 (1H, dd, J petroleum
ether)
gave
methyl
(2S)-2-
18.0, 4.2 Hz, 3-HH), 3.77 (3H, s, OCH3), 4.71 (1H, dt, J 8.5, [(benzyloxycarbonyl)amino]-3-[5’-(4”-nitrophenyl)-1’-phenyl-
4.2 Hz, 2-H), 5.13 (2H, s, OCH2Ph), 5.87 (1H, d, J 8.5 Hz, 1’H-pyrazol-3’-yl]propanoate (18) as a yellow oil (0.14 g,
NH), 6.77 (1H, d, J 16.2 Hz, 5-H), 7.28−7.39 (5H, m, Ph), 7.61 76%). νmax/cm−1 (neat) 3350 (NH), 2951 (CH), 1717 (C=O),
(1H, d, J 16.2 Hz, 6-H), 7.64−7.70 (5H, m, 2’-H, 3’-H, 5’-H, 1597, 1502 (C=C), 1346, 1207, 1051, 972, 853; [α]D23 +30.0 (c
6’-H and 5”-H), 7.94 (1H, ddd, J 7.8, 2.0, 1.0 Hz, 6”-H), 8.24 0.3, CHCl3); δH (400 MHz, CDCl3) 3.21−3.34 (2H, m, 3-H2),
(1H, ddd, J 8.2, 2.0, 1.0 Hz, 4”-H), 8.48 (1H, t, J 2.0 Hz, 2”-H); 3.77 (3H, s, OCH3), 4.76 (1H, dt, J 8.2, 5.6 Hz, 2-H), 5.09 (1H,
δC (101 MHz, CDCl3) 42.6 (CH2), 50.2 (CH), 52.9 (CH3), 67.2 d, J 12.2 Hz, OCHHPh), 5.14 (1H, d, J 12.2 Hz, OCHHPh),
(CH2), 122.0 (CH), 122.8 (CH), 126.2 (CH), 127.9 (2 × CH), 5.72 (1H, d, J 8.2 Hz, NH), 6.41 (1H, s, 4’-H), 7.18–7.23 (2H,
128.2 (2 × CH), 128.3 (CH), 128.7 (2 × CH), 129.4 (2 × CH), m, ArH), 7.29–7.38 (10H, m, 2”-H, 6”-H and ArH), 8.14 (2H,
130.1 (CH), 133.0 (CH), 134.5 (C), 136.4 (C), 141.0 (C), 141.8 d, J 8.7 Hz, 3”-H and 5”-H); δC (101 MHz, CDCl3) 30.7 (CH2),
(C), 143.1 (CH), 149.0 (C), 156.2 (C), 171.7 (C), 197.4 (C); m/z 52.7 (CH3), 53.5 (CH), 67.1 (CH2), 108.8 (CH), 123.9 (2 ×
(CI) 489.1664 (MH+. C27H25N2O7 requires 489.1662), 459 CH), 125.3 (2 × CH), 128.2 (CH), 128.3 (CH), 128.3 (2 × CH),
(8%), 418 (10), 381 (42), 351 (23), 338 (32), 310 (19), 275 128.6 (2 × CH), 129.4 (4 × CH), 136.4 (C), 136.6 (C), 139.5
(10), 181 (15), 147 (26), 91 (100).
Methyl
(2S)-2-[(benzyloxycarbonyl)amino]-3-(1’,5’- (EI) 500.1695 (M+. C27H24N4O6 requires 500.1696), 441 (10%),
diphenyl-1’H-pyrazol-3’-yl)propanoate (17). To a solution of 392 (15), 349 (100), 278 (68), 232 (22), 91 (47).
methyl (2S,5E)-2-[(benzyloxycarbonyl)amino]-4-oxo-6- Methyl (2S)-2-[(benzyloxycarbonyl)amino]-3-[5’-(4”-
(C), 141.6 (C), 147.5 (C), 148.9 (C), 156.1 (C), 172.0 (C); m/z
phenylhex-5-enoate (12) (0.17 g, 0.46 mmol) in methanol (4 methoxyphenyl)-1’-phenyl-1’H-pyrazol-3’-yl]propanoate
mL) was added phenylhydrazine (0.05 mL, 0.46 mmol) and (19). The reactions were carried out as described for 12 using
37% aqueous hydrochloric acid (0.02 mL). The reaction methyl
(2S,5E)-2-[(benzyloxycarbonyl)amino]-6-(4’-
mixture was stirred under reflux for 17 h, cooled to room methoxyphenyl)-4-oxohex-5-enoate (14). Purification by
temperature and concentrated in vacuo. The resulting material column chromatography (elution with 20–30% ethyl acetate in
was diluted with ethyl acetate (10 mL) and a saturated aqueous petroleum
ether)
gave
methyl
(2S)-2-
solution of sodium hydrogen carbonate (10 mL), extracted with [(benzyloxycarbonyl)amino]-3-[5’-(4”-methoxyphenyl)-1’-
ethyl acetate (3 × 10 mL), dried (MgSO4) and concentrated in phenyl-1’H-pyrazol-3’-yl]propanoate (19) as a colourless oil
vacuo. The resulting material was then dissolved in (0.07 g, 75%). νmax/cm−1 (neat) 3339 (NH), 2951 (CH), 1717
26
dichloromethane (30 mL) and 2,3-dichloro-5,6-dicyano-1,4- (C=O), 1506 (C=C), 1498, 1436, 1248, 1176, 1027, 835; [α]D
benzoquinone (0.10 g, 0.46 mmol) was added. After stirring at +10.6 (c 0.5, CHCl3); δH (400 MHz, CDCl3) 3.23 (1H, dd, J
room temperature for
2 h, the reaction mixture was 14.8, 4.9 Hz, 3-HH), 3.30 (1H, dd, J 14.8, 5.7 Hz, 3-HH), 3.78
concentrated in vacuo and the resulting solid purified by (3H, s, OCH3), 3.81 (3H, s, OCH3), 4.72−4.78 (1H, m, 2-H),
column chromatography (elution with 20−30% ethyl acetate in 5.11 (1H, d, J 12.3 Hz, OCHHPh), 5.15 (1H, d, J 12.3 Hz,
petroleum ether), followed by triturating with chloroform to OCHHPh), 5.80 (1H, d, J 8.3 Hz, NH), 6.22 (1H, s, 4’-H), 6.82
give
methyl
(2S)-2-[(benzyloxycarbonyl)amino]-3-(1’,5’- (2H, d, J 8.8 Hz, 3”-H and 5”-H), 7.11 (2H, d, J 8.8 Hz, 2”-H
diphenyl-1’H-pyrazol-3’-yl)propanoate (17) as a colourless oil and 6”-H), 7.22−7.38 (10H, m, 2 × Ph); δC (101 MHz, CDCl3)
(0.16 g, 76%). νmax/cm−1 (neat) 3379 (NH), 2951 (CH), 1717 30.8 (CH2), 52.6 (CH3), 53.6 (CH), 55.4 (CH3), 67.0 (CH2),
23
(C=O), 1503 (C=C), 1375, 1207, 1051, 912, 761; [α]D +29.2 107.1 (CH), 114.0 (2 × CH), 122.9 (C), 125.2 (2 × CH), 127.3
(c 0.3, CHCl3); δH (400 MHz, CDCl3) 3.23 (1H, dd, J 14.9, 4.9 (CH), 128.2 (3 × CH), 128.6 (2 × CH), 128.9 (2 × CH), 130.1
Hz, 3-HH), 3.30 (1H, dd, J 14.9, 5.8 Hz, 3-HH), 3.77 (3H, s, (2 × CH), 136.5 (C), 140.1 (C), 143.9 (C), 148.2 (C), 156.1 (C),
OCH3), 4.71–4.79 (1H, m, 2-H), 5.10 (1H, d, J 12.2 Hz, 159.7 (C), 172.2 (C); m/z (EI) 485.1961 (M+. C28H27N3O5
OCHHPh), 5.14 (1H, d, J 12.2 Hz, OCHHPh), 5.77 (1H, d, J requires 485.1951), 426 (31%), 377 (27), 334 (100), 318 (17),
8.4 Hz, NH), 6.27 (1H, s, 4’-H), 7.15–7.36 (15H, m, 3 × Ph); δC 263 (61), 199 (18), 91 (33).
(101 MHz, CDCl3) 30.7 (CH2), 52.5 (CH3), 53.6 (CH), 67.0 Methyl
(2S)-2-[(benzyloxycarbonyl)amino]-3-[5’-
(CH2), 107.6 (CH), 125.2 (2 × CH), 127.4 (CH), 128.2 (3 × (naphthalen-2”-yl)-1’-phenyl-1’H-pyrazol-3’-yl]propanoate
CH), 128.4 (CH), 128.5 (2 × CH), 128.6 (2 × CH), 128.8 (2 × (20). The reactions were carried out as described for 12 using
CH), 128.9 (2 × CH), 130.5 (C), 136.5 (C), 140.0 (C), 144.0 methyl (2S,5E)-2-[(benzyloxycarbonyl)amino]-6-(naphthalen-
(C), 148.3 (C), 156.1 (C), 172.1 (C); m/z (CI) 456.1925 (MH+. 2’-yl)-4-oxohex-5-enoate (15) (0.15 g, 0.36 mmol). Purification
C27H26N3O4 requires 456.1923), 368 (9%), 348 (100), 305 (11), by column chromatography (elution with 20% ethyl acetate in
257 (23) 137 (59).
petroleum
ether)
gave
methyl
(2S)-2-
[(benzyloxycarbonyl)amino]-3-[5’-(naphthalen-2”-yl)-1’-
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 7 of 10
Journal Name
Organic & Biomolecular Chemistry
ARTICLE
phenyl-1’H-pyrazol-3’-yl]propanoate (20) as a white solid aqueous hydrochloric acid (5 mL) and the mixture stirred under
(0.13 g, 73%). Mp 66−67 °C; νmax/cm−1 (neat) 3341 (NH), 2924 reflux for 24 h. The mixture was cooled and concentrated in
View Article Online
(CH), 1719 (C=O), 1597, 1499 (C=C), 1207, 1047, 818, 748; vacuo. Trituration with diethyl ether gave (2S)-2-amino-3-
DOI: 10.1039/C5OB00364D
25
[α]D +14.0 (c 0.2, CHCl3); δH (400 MHz, CDCl3) 3.27 (1H, (1’,5’-diphenyl-1’H-pyrazol-3’-yl)propanoic
acid
dd, J 15.0, 4.7 Hz, 3-HH), 3.33 (1H, dd, J 15.0, 5.7 Hz, 3-HH), hydrochloride (22) as a white foam (0.05 g, 88%). νmax/cm−1
3.79 (3H, s, OCH3), 4.73−4.82 (1H, m, 2-H), 5.10 (1H, d, J (neat) 3380 (NH), 3058 (CH), 1631 (C=O), 1596, 1503 (C=C),
28
12.3 Hz, OCHHPh), 5.15 (1H, d, J 12.3 Hz, OCHHPh), 5.81 1424, 1375, 1112, 761; [α]D −25.8 (c 0.4, MeOH); δH (400
(1H, d, J 8.1 Hz, NH), 6.38 (1H, s, 4’-H), 7.19 (1H, dd, J 8.5, MHz, CD3OD) 3.20−3.45 (2H, m, 3-H2), 4.02 (1H, br s, 2-H),
1.6 Hz, 3”-H), 7.24−7.38 (10H, m, 2 × Ph), 7.46−7.53 (2H, m, 6.53 (1H, s, 4’-H), 7.17−7.40 (10H, m, 2 × Ph); δH (126 MHz,
6”-H and 7”-H), 7.69−7.84 (4H, m, 1”-H, 4”-H, 5”-H and 8”- CD3OD) 30.3 (CH2), 55.7 (CH), 108.7 (CH), 126.7 (2 × CH),
H); δC (101 MHz, CDCl3) 30.8 (CH2), 52.7 (CH3), 53.6 (CH), 129.0 (CH), 129.6 (3 × CH), 129.8 (2 × CH), 130.1 (2 × CH),
67.1 (CH2), 108.0 (CH), 125.2 (2 × CH), 126.4 (CH), 126.7 131.5 (C), 141.3 (C), 145.9 (C), 150.0 (C), 173.8 (C); m/z (ESI)
(CH), 126.8 (CH), 127.5 (CH), 127.9 (CH), 127.9 (C), 128.1 308.1382 (MH+. C18H18N3O2 requires 308.1394).
(CH), 128.2 (CH), 128.2 (3 × CH), 128.3 (CH), 128.6 (2 × CH), (2S)-2-Amino-3-[5’-(4”-methoxyphenyl)-1’-phenyl-1’H-
129.1 (2 × CH), 132.9 (C), 133.2 (C), 136.5 (C), 141.1 (C), pyrazol-3’-yl]propanoic acid hydrochloride (23). The
144.0 (C), 148.5 (C), 156.2 (C), 172.1 (C); m/z (EI) 505.2012 reactions were carried out as described for 17 using methyl
(M+. C31H27N3O4 requires 505.2002), 446 (10%), 397 (55), 354 (2S)-2-[(benzyloxycarbonyl)amino]-3-[5’-(4”-methoxyphenyl)-
(45), 338 (20), 283 (100), 215 (10), 108 (13), 91 (27).
Methyl (2S)-2-[(benzyloxycarbonyl)amino]-3-[5’-(3”’- mmol). This gave (2S)-2-amino-3-[5’-(4”-methoxyphenyl)-1’-
nitrobiphen-4”-yl)-1’-phenyl-1’H-pyrazol-3’-yl]propanoate phenyl-1’H-pyrazol-3’-yl]propanoic acid hydrochloride (23) as
(21). The reactions were carried out as described for 12 using a white foam (0.04 g, 79%). νmax/cm−1 (neat) 3359 (NH), 2921
methyl (2S,5E)-2-[(benzyloxycarbonyl)amino]-6-(3”- (CH), 1729 (C=O), 1611, 1506 (C=C), 1499, 1437, 1151, 834;
1’-phenyl-1’H-pyrazol-3’-yl]propanoate (19) (0.07 g, 0.14
28
nitrobiphen-4’-yl)-4-oxohex-5-enoate (16) (0.20 g, 0.41 mmol). [α]D −25.0 (c 0.2, CHCl3); δH (500 MHz, CD3OD) 3.32 (1H,
Purification by column chromatography (elution with 20% dd, J 16.0, 7.5 Hz, 3-HH), 3.42 (1H, dd, J 16.0, 4.4 Hz, 3-HH),
ethyl acetate in petroleum ether) gave methyl (2S)-2- 3.78 (3H, s, OCH3), 4.38−4.43 (1H, m, 2-H), 6.46 (1H, s, 4’-H),
[(benzyloxycarbonyl)amino]-3-[5’-(3”’-nitrobiphen-4”-yl)-1’-
6.86 (2H, d, J 8.7 Hz, 3”-H and 5”-H), 7.14 (2H, d, J 8.7 Hz,
phenyl-1’H-pyrazol-3’-yl]propanoate (21) as a yellow oil (0.20 2”-H and 6”-H), 7.27−7.42 (5H, m, Ph); δC (126 MHz,
g, 84%). νmax/cm−1 (neat) 3359 (NH), 2922 (CH), 1716 (C=O), CD3OD) 29.6 (CH2), 53.7 (CH), 55.9 (CH3), 108.0 (CH), 115.1
1508 (C=C), 1500, 1348, 1207, 1052, 803, 727; [α]D23 +20.5 (c (2 × CH), 123.6 (C), 126.6 (2 × CH), 129.0 (CH), 130.1 (2 ×
0.4, CHCl3); δH (400 MHz, CDCl3) 3.26 (1H, dd, J 15.0, 4.9 CH), 131.2 (2 × CH), 141.3 (C), 146.3 (C), 148.3 (C), 161.6
Hz, 3-HH), 3.32 (1H, dd, J 15.0, 5.6 Hz, 3-HH), 3.79 (3H, s, (C), 171.0 (C); m/z (ESI) 338.1489 (MH+. C19H20N3O3 requires
OCH3), 4.73−4.81 (1H, m, 2-H), 5.11 (1H, d, J 12.3 Hz, 338.1499).
OCHHPh), 5.15 (1H, d, J 12.3 Hz, OCHHPh), 5.78 (1H, d, J (2S)-2-Amino-3-[5’-(naphthalen-2”-yl)-1’-phenyl-1’H-
8.3 Hz, NH), 6.36 (1H, s, 4’-H), 7.26−7.39 (12H, m, 2”-H, 6”- pyrazol-3’-yl]propanoic acid hydrochloride (24). The
H and 2 × Ph), 7.56 (2H, d, J 8.3 Hz, 3”-H and 5”-H), 7.62 (1H, reactions were carried out as described for 17 using (2S)-2-
t, J 8.0 Hz, 5”’-H), 7.88−7.93 (1H, m, 6”’-H), 8.21 (1H, ddd, J [(benzyloxycarbonyl)amino]-3-[5’-(naphthalen-2”-yl)-1’-
8.0, 1.9, 0.8 Hz, 4”’-H), 8.44 (1H, t, J 1.9 Hz, 2”’-H); δC (101 phenyl-1’H-pyrazol-3’-yl]propanoate (20) (0.03 g, 0.06 mmol).
MHz, CDCl3) 30.8 (CH2), 52.7 (CH3), 53.6 (CH), 67.1 (CH2), This gave (2S)-2-amino-3-[5’-(naphthalen-2”-yl)-1’-phenyl-
107.9 (CH), 122.0 (CH), 122.5 (CH), 125.3 (2 × CH), 127.3 (2 1’H-pyrazol-3’-yl]propanoic acid hydrochloride (24) as an off-
× CH), 127.8 (CH), 128.3 (3 × CH), 128.7 (2 × CH), 129.2 (2 × white foam (0.02 g, 83%). νmax/cm−1 (neat) 3366 (NH), 2922
CH), 129.5 (2 × CH), 130.0 (CH), 130.7 (C), 133.0 (CH), 136.5 (CH), 1739 (C=O), 1596 (C=C), 1498, 1205, 1081, 819, 752;
28
(C), 138.6 (C), 140.1 (C), 142.0 (C), 143.3 (C), 148.5 (C), [α]D −33.7 (c 0.3, MeOH); δH (400 MHz, CD3OD) 3.40 (1H,
148.9 (C), 156.1 (C), 172.2 (C); m/z (EI) 576.2007 (M+. dd, J 15.8, 7.3 Hz, 3-HH), 3.49 (1H, br d, J 15.8 Hz, 3-HH),
C33H28N4O6 requires 576.2009), 468 (45%), 425 (15), 409 (26), 4.44−4.51 (1H, m, 2-H), 6.70 (1H, s, 4’-H), 7.25 (1H, br d, J
381 (17), 354 (100), 308 (17), 202 (6), 159 (9), 77 (18).
(2S)-2-Amino-3-(1’,5’-diphenyl-1’H-pyrazol-3’-
8.2 Hz, 3”-H), 7.32−7.42 (5H, m, Ph), 7.46−7.54 (2H, m, 6”-H
and 7”-H), 7.72−7.87 (4H, m, 1”-H, 4”-H, 5”-H and 8”-H); δC
yl)propanoic acid hydrochloride (22). To a solution of methyl (101 MHz, CD3OD) 29.6 (CH2), 53.5 (CH), 109.0 (CH), 126.7
(2S)-2-[(benzyloxycarbonyl)amino]-3-(1’,5’-diphenyl-1’H- (2 × CH), 127.0 (CH), 127.8 (CH), 128.1 (CH), 128.5 (C),
pyrazol-3’-yl)propanoate (17) (0.09 g, 0.19 mmol) in methanol 128.7 (CH), 129.2 (CH), 129.3 (2 × CH), 129.3 (CH) 130.2 (2 ×
and water (5 mL, 7:3) was added cesium carbonate (0.08 g, CH), 134.4 (2 × C), 140.9 (C), 146.3 (C), 148.4 (C), 171.0 (C);
0.25 mmol). The reaction mixture was stirred at room m/z (ESI) 358.1541 (MH+. C22H20N3O2 requires 358.1550).
temperature for 16 h before concentrating in vacuo. The (2S)-2-Amino-3-[5’-(4”-nitrophenyl)-1’-phenyl-1’H-pyrazol-
resulting residue was dissolved in water (10 mL), acidified to 3’-yl]propanoic acid hydrochloride (25). To a solution of
pH 1 with 1.0 M aqueous hydrochloric acid, extracted with methyl
dichloromethane (3 × 10 mL), dried (MgSO4) and concentrated nitrophenyl)-1’-phenyl-1’H-pyrazol-3’-yl]propanoate
in vacuo. The resulting residue was suspended in 6.0 M (0.08 g, 0.16 mmol) in methanol (0.5 mL) was added 6.0 M
(2S)-2-[(benzyloxycarbonyl)amino]-3-[5’-(4”-
(18)
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 7

Organic & Biomolecular Chemistry
Page 8 of 10
Journal Name
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21
aqueous hydrochloric acid (4.5 mL). The reaction mixture was (C=O), 1597, 1518, 1502, 1346, 1219, 853, 752, 696; [α]D
then stirred under reflux for 48 h. After cooling to room +11.5 (c 0.9, CDCl3); δH (500 MHz, CDCl3) 2.94 (1H, dd, J
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temperature, the mixture was concentrated in vacuo and 14.8, 6.1 Hz, 3-HH), 3.00 (1H, dd, J 14.D8O, I6:.160.H10z3,9/3C-5HOHB0)0, 336.40D6
triturated with diethyl ether to give (2S)-2-amino-3-[5’-(4”- (1H, br s, OH), 3.62−3.76 (2H, m, 1-H2), 3.96−4.06 (1H, m, 2-
nitrophenyl)-1’-phenyl-1’H-pyrazol-3’-yl]propanoic
acid H), 5.02 (1H, d, J 12.3 Hz, OCHHPh), 5.05 (1H, d, J 12.3 Hz,
hydrochloride (25) as a pale yellow foam (0.06 g, 97%). OCHHPh), 5.37 (1H, d, J 7.0 Hz, NH), 6.42 (1H, s, 4’-H),
νmax/cm−1 (neat) 3400 (NH), 2918 (CH), 2850, 1744 (C=O), 7.12−7.17 (2H, m, 2”-H and 6”-H), 7.20−7.33 (10H, m, 2 ×
27
1596 (C=C), 1515, 1502, 1344, 1255, 1080, 854; [α]D −16.0 Ph), 8.05−8.09 (2H, m, 3”-H and 5”-H); δC (126 MHz, CDCl3)
(c 0.3, MeOH); δH (400 MHz, CD3OD) 3.33−3.51 (2H, m, 3- 30.1 (CH2), 52.2 (CH), 64.6 (CH2), 66.8 (CH2), 109.1 (CH),
H2), 4.41−4.48 (1H, m, 2-H), 6.73 (1H, s, 4’-H), 7.29−7.46 123.8 (2 × CH), 125.3 (2 × CH), 128.1 (CH), 128.2 (CH), 128.3
(5H, m, Ph), 7.48 (2H, d, J 7.7 Hz, 2”-H and 6”-H), 8.19 (2H, (2 × CH), 128.5 (2 × CH), 129.2 (2 × CH), 129.4 (2 × CH),
d, J 7.7 Hz, 3”-H and 5”-H); δC (101 MHz, CD3OD) 29.6 136.4 (C), 136.4 (C), 139.2 (C), 141.6 (C), 147.4 (C), 150.2
(CH2), 53.5 (CH), 109.9 (CH), 124.7 (2 × CH), 126.8 (2 × CH), (C), 156.5 (C); m/z (ESI) 495.1632 (MNa+. C26H24N4NaO5
129.6 (CH), 130.4 (2 × CH), 130.8 (2 × CH), 137.5 (C), 140.6 requires 495.1639).
(C), 143.8 (C), 148.7 (C), 148.9 (C), 170.9 (C); m/z (ESI) (2S)-2-[(Benzyloxycarbonyl)amino]-1-methanesulfonate-3-
351.1082 ([M–H]–. C18H15N4O4 requires 351.1099).
[5’-(4”-nitrophenyl)-1’-phenyl-1’H-pyrazol-3’-yl]propane
(28). (2S)-2-[(Benzyloxycarbonyl)amino]-3-[5’-(4”-
(27)
reaction was carried out as described for 18 using methyl (2S)- (2.56 g, 5.42 mmol) was dissolved in dichloromethane (64 mL)
2-[(benzyloxycarbonyl)amino]-3-[5’-(3”’-nitrobiphen-4”-yl)- and cooled to 0 °C. Methanesulfonyl chloride (0.63 mL,
(2S)-2-Amino-3-[5’-(3”’-nitrobiphen-4”-yl)-1’-phenyl-1’H-
pyrazol-3’-yl]propanoic acid hydrochloride (26). The nitrophenyl)-1’-phenyl-1’H-pyrazol-3’-yl]propan-1-ol
1’-phenyl-1’H-pyrazol-3’-yl]propanoate (21) (0.15 g, 0.26 8.13 mmol) and triethylamine (1.21 mL, 8.67 mmol) were
mmol). This gave (2S)-2-amino-3-[5’-(3”’-nitrobiphen-4”-yl)- added dropwise and the reaction mixture stirred at room
1’-phenyl-1’H-pyrazol-3’-yl]propanoic acid hydrochloride (26) temperature for 0.5 h. Dichloromethane (50 mL) was added to
as an off-white foam (0.12 g, 98%). νmax/cm−1 (neat) 3026 the reaction mixture, which was then washed with 1 M aqueous
(NH), 2861 (CH), 1731 (C=O), 1526 (C=C), 1500, 1347, 1198, potassium hydrogensulfonate (100 mL), water (100 mL), brine
28
973, 803, 726; [α]D −38.3 (c 0.3, MeOH); δH (400 MHz, (100 mL) and dried (MgSO4). The solvent was removed in
CD3OD) 3.37 (1H, dd, J 15.8, 7.5 Hz, 3-HH), 3.46 (1H, dd, J vacuo and gave 28 as a colourless solid (2.72 g, 92%).
15.8, 4.6 Hz, 3-HH), 4.45 (1H, dd, J 7.5, 4.6 Hz, 2-H), 6.64 νmax/cm−1 (neat) 3270 (NH), 3028 (CH), 1713 (C=O), 1597,
23
(1H, s, 4’-H), 7.33−7.45 (7H, m, 2”-H, 6”-H and Ph), 1518, 1502, 1346, 1172, 963, 750, 696; [α]D −7.1 (c 0.8,
7.66−7.73 (3H, m, 3”-H, 5”-H and 5”’-H), 8.04 (1H, ddd, J 7.8, CDCl3); δH (400 MHz, CDCl3) 2.94 (3H, s, SO2CH3), 3.00 (2H,
2.0, 0.9 Hz, 6”’-H), 8.23 (1H, ddd, J 8.2, 2.0, 0.9 Hz, 4”’-H), d, J 5.1 Hz, 3-H2), 4.22−4.33 (3H, m, 1-H2 and 2-H), 5.04 (2H,
8.46 (1H, t, J 2.0 Hz, 2”’-H); δC (101 MHz, CD3OD) 29.6 s, OCH2Ph), 5.41 (1H, br s, NH), 6.44 (1H, s, 4’-H), 7.13−7.18
(CH2), 53.6 (CH), 108.8 (CH), 122.5 (CH), 123.4 (CH), 126.8 (2H, m, 2”-H and 6”-H), 7.21−7.33 (10H, m, 2 × Ph),
(2 × CH), 128.4 (2 × CH), 129.3 (CH), 130.3 (2 × CH), 130.6 8.05−8.12 (2H, m, 3”-H and 5”-H); δC (101 MHz, CDCl3) 29.4
(2 × CH), 131.3 (CH), 131.5 (C), 134.1 (CH), 140.2 (C), 141.1 (CH2), 37.4 (CH3), 49.8 (CH), 67.0 (CH2), 69.6 (CH2), 109.0
(C), 143.0 (C), 145.5 (C), 148.5 (C), 150.3 (C), 171.0 (C); m/z (CH), 123.8 (2 × CH), 125.3 (2 × CH), 128.1 (2 × CH), 128.3
(ESI) 429.1545 (MH+. C24H21N4O4 requires 429.1557).
(2 × CH), 128.6 (2 × CH), 129.3 (2 × CH), 129.3 (2 × CH),
(2S)-2-[(Benzyloxycarbonyl)amino]-3-[5’-(4”-nitrophenyl)-
136.3 (C), 136.4 (C), 139.3 (C), 141.7 (C), 147.4 (C), 149.0
1’-phenyl-1’H-pyrazol-3’-yl]propan-1-ol (27). Methyl (2S)-2- (C), 155.8 (C); m/z (ESI) 573.1389 (MNa+. C27H26N4NaO7S
[(benzyloxycarbonyl)amino]-3-[5’-(4”-nitrophenyl)-1’-phenyl-
requires 573.1414).
1’H-pyrazol-3’-yl]propanoate (18) (2.90 g, 5.79 mmol) was (2S)-2-[(Benzyloxycarbonyl)amino]-3-[5’-(4”-nitrophenyl)-
dissolved in THF (25 mL) under an atmosphere of argon at 1’-phenyl-1’H-pyrazol-3’-yl]-1-thioacetylpropane
room temperature. Lithium chloride (0.61 g, 14.5 mmol) was Thioacetic acid (0.78 mL, 10.9 mmol) was added to a
added, followed by sodium borohydride (0.55 g, 14.5 mmol, suspension of cesium carbonate (1.77 g, 5.43 mmol) in DMF
(29).
2.50 eq.) and the mixture was stirred for 0.1 h. Ethanol (34 mL) (5 mL).
This
solution
was
added
to
(2S)-2-
was added and the cloudy mixture stirred for 7 h at room [(benzyloxycarbonyl)amino]-1-methanesulfonate-3-[5’-(4”-
temperature. The reaction mixture was cooled to 0 °C and nitrophenyl)-1’-phenyl-1’H-pyrazol-3’-yl]propane (28) (2.72 g,
quenched with a saturated solution of ammonium chloride 4.94 mmol) in DMF (10 mL) under an atmosphere of argon.
(28 mL) and water (81 mL). The solution was extracted with The reaction mixture was stirred overnight in the dark at room
ethyl acetate (3 × 100 mL). The combined organic phases were temperature. Ethyl acetate (50 mL) and water (50 mL) were
dried (MgSO4) and the solvent removed in vacuo. Purification added and the organic layer was washed with 1 M aqueous
by column chromatography (gradient elution with ethyl acetate potassium hydrogensulfate (100 mL), 1 M aqueous sodium
in petroleum ether, 1:1 to 7:3) gave (2S)-2- hydrogencarbonate (100 mL), brine (100 mL) and dried
[(benzyloxycarbonyl)amino]-3-[5’-(4”-nitrophenyl)-1’-phenyl-
1’H-pyrazol-3’-yl]propan-1-ol (27) as colourless solid purified by column chromatography (30% ethyl acetate in
(2.60 g, 95%). νmax/cm−1 (neat) 3335 (OH), 2934 (CH), 1697 petroleum ether). (2S)-2-[(Benzyloxycarbonyl)amino]-3-[5’-
(MgSO4). The solvents were evaporated and the crude product
a
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 9 of 10
Journal Name
Organic & Biomolecular Chemistry
ARTICLE
(4”-nitrophenyl)-1’-phenyl-1’H-pyrazol-3’-yl]-1-
CDCl3) 60.2 (1F, s, SO2F); m/z (ESI) 561.1192 (MNa+.
thioacetylpropane (29) was obtained as a slightly orange- C26H23FN4NaO6S requires 561.1215).
brownish solid (2.22 g, 85%). νmax/cm−1 (neat) 3355 (NH), 3075
View Article Online
DOI: 10.1039/C5OB00364D
(CH), 1694 (C=O), 1597, 1518, 1503, 1347, 1252, 1133, 853,
754; [α]D −3.2 (c 0.7, CDCl3); δH (500 MHz, CDCl3) 2.27
Acknowledgements
21
Financial support from SINAPSE (studentship to LG), the
University of Glasgow (studentship to RA) and the EPSRC
(studentship to AHH, EP/K503058) is gratefully acknowledged.
(3H, s, COCH3), 2.94 (2H, d, J 6.2 Hz, 3-H2), 3.06−3.18 (2H,
m, 1-H2), 4.07−4.18 (1H, m, 2-H), 5.01 (2H, s, OCH2Ph), 5.41
(1H, d, J 8.2 Hz, NH), 6.42 (1H, s, 4’-H), 7.14−7.18 (2H, m,
2”-H and 6”-H), 7.20−7.33 (10H, m, 2 × Ph), 8.04−8.10 (2H,
m, 3”-H and 5”-H); δC (101 MHz, CDCl3) 30.6 (CH3), 32.5
(CH2), 33.1 (CH2), 51.0 (CH), 66.6 (CH2), 108.9 (CH), 123.8 (2
× CH), 125.3 (2 × CH), 128.0 (CH), 128.1 (CH), 128.1 (2 ×
CH), 128.5 (2 × CH), 129.2 (2 × CH), 129.3 (2 × CH), 136.6
(C), 139.4 (C), 141.5 (2 × C), 147.3 (C), 149.7 (C), 156.0 (C),
195.7 (C); m/z (ESI) 553.1502 (MNa+. C28H26N4NaO5S
requires 553.1516).
(2S)-2-[(Benzyloxycarbonyl)amino]-1-fluorosulfonyl-3-[5’-
(4”-nitrophenyl)-1’-phenyl-1’H-pyrazol-3’-yl]propane (31).
(2S)-2-[(Benzyloxycarbonyl)amino]-3-[5’-(4”-nitrophenyl)-1’-
phenyl-1’H-pyrazol-3’-yl]-1-thioacetylpropane (29) (2.22 g,
4.18 mmol) was dissolved in acetic acid (15 mL) and 30%
hydrogen peroxide (4.8 mL) was added and stirred overnight at
room temperature. Sodium acetate (0.34 g, 4.18 mmol) was
added and the mixture stirred for 1 h. DMF (5 mL) was added
and the solution was partially concentrated in vacuo. This
procedure was repeated three more times until the DMF was
removed completely. After co-evaporation twice with water and
Notes and references
a
WestCHEM, School of Chemistry, The Joseph Black Building,
University of Glasgow, Glasgow, G12 8QQ, UK. E-mail:
Andrew.Sutherland@glasgow.ac.uk; Tel: +44 (0)141 330 5936.
b
Department of Medicinal Chemistry and Chemical Biology, Faculty of
Science, Utrecht University, P. O. Box 80082, 3508 TB, Utrecht, The
Netherlands.
† Electronic Supplementary Information (ESI) available: experimental
procedures and data for all known compounds and NMR spectra for all
new compounds. See DOI: 10.1039/b000000x/
1
For reviews see: (a) I. Wagner and H. Musso, Angew. Chem. Int. Ed.
Engl., 1983, 22, 816. (b) J. P. Greenstein and M. Winitz, Chemistry
of the Amino Acids; R. E. Krieger, FL 1984, Vols. 1–3. (c) G. C.
Barrett, Ed. Chemistry and Biochemistry of the Amino Acids,
Chapman and Hall: London, 1985. (d) M. J. O’Donnell, Ed. α-Amino
Acid Synthesis, Tetrahedron, 1988, 44, 5253. (e) R. M. Williams,
Synthesis of Optically Active α-Amino Acids, Pergamon Press,
Oxford, 1989; Vol. 7.
three
[(benzyloxycarbonyl)amino]-3-[5’-(4”-nitrophenyl)-1’-phenyl-
1’H-pyrazol-3’-yl]propane-1-sulfonate was obtained as
yellow solid (2.37 g, 100%). quantity of (2S)-2-
times
with
toluene,
sodium
(2S)-2-
2
(a) Y. Ohfune, Acc. Chem. Res., 1992, 25, 360. (b) A. Sutherland and
C. L. Willis, Nat. Prod. Rep., 2000, 17, 621. (c) D. A. Dougherty,
Curr. Opin. Chem. Biol., 2000, 4, 645. (d) Y. Ohfune and T. Shinada,
Eur. J. Org. Chem., 2005, 5127. (e) H. Vogt and S. Bräse, Org.
Biomol. Chem., 2007, 5, 406. (f) R. Smits, C. D. Cadicamo, K.
Burger and B. Koksch, Chem. Soc. Rev., 2008, 37, 1727. (g) M.
Mortensen, R. Husmann, E. Veri and C. Bolm, Chem. Soc. Rev.,
2009, 38, 1002. (h) K. Lang and J. W. Chin, Chem. Rev., 2014, 114,
4764.
a
A
[(benzyloxycarbonyl)amino]-3-[5’-(4”-nitrophenyl)-1’-phenyl-
1’H-pyrazol-3’-yl]propane-1-sulfonate (0.20 g, 0.36 mmol) was
dissolved in dichloromethane (15 mL) under an atmosphere of
argon and XtalFluor-M® (30) (0.16 g, 644 µmol) and
triethylamine trihydrofluoride (2.5 µL, 15.4 µmol) were added.
The reaction mixture was heated under reflux for 20 h. Silica
was added to quench the reaction and the solvent removed in
vacuo. Purification by column chromatography (40% ethyl
3
4
5
6
7
For example, see: (a) C. J. Easton, Chem. Rev., 1997, 97, 53. (b) C.
Nájera and J. M. Sansano, Chem. Rev., 2007, 107, 4584. (c) A. F. M.
Noisier and M. A. Brimble, Chem. Rev., 2014, 114, 8775.
(a) P. Kolar, A. Petrič and M. Tišler, J. Heterocyclic Chem., 1997,
34, 1067. (b) P. Singh, K. Samanta, S. K. Das and G. Panda, Org.
Biomol. Chem., 2014, 12, 6297.
acetate
[(benzyloxycarbonyl)amino]-1-fluorosulfonyl-3-[5’-(4”-
nitrophenyl)-1’-phenyl-1’H-pyrazol-3’-yl]propane (31) as
in
petroleum
ether)
gave
(2S)-2-
a
yellow solid (0.123 g, 64%). νmax/cm−1 (neat) 3337 (NH), 2930
(CH), 1699 (C=O), 1598, 1538, 1515, 1407, 1388, 1347, 1265,
1195, 1050, 973, 854; [α]D20 +5.0 (c 1.0, CDCl3); δH (400 MHz,
CDCl3) 3.10−3.24 (2H, m, 3-H2), 3.70 (1H, dt, J 14.6, 5.7 Hz,
1-HH), 3.91 (1H, dd, J 14.6, 5.7 Hz, 1-HH), 4.52−4.63 (1H, m,
2-H), 5.06 (2H, s, OCH2Ph), 5.73 (1H, d, J 8.0 Hz, NH), 6.43
(1H, s, 4’-H), 7.13−7.18 (2H, m, 2”-H and 6”-H), 7.23−7.37
(10H, m, 2 × Ph), 8.06−8.12 (2H, m, 3”-H and 5”-H); δC (126
MHz, CDCl3) 31.2 (CH2), 46.9 (CH), 53.2 (CH2, d, JC-S-F 15.1
Hz), 67.2 (CH2), 109.3 (CH), 123.8 (2 × CH), 125.2 (2 × CH),
128.2 (2 × CH), 128.3 (CH), 128.4 (CH), 128.6 (2 × CH), 129.3
(2 × CH), 129.4 (2 × CH), 136.0 (C), 136.1 (C), 139.1 (C),
141.8 (C), 147.5 (C), 148.4 (C), 155.4 (C); δF (377 MHz,
(a) S. Shinano and T. Kaya, J. Agric. Chem. Soc. Japan, 1957, 31,
759. (b) C. N. Farthing, J. E. Baldwin, A. T. Russell, C. J. Schofield
and A. C. Spivey, Tetrahedron Lett., 1996, 37, 5225.
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This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 9

Organic & Biomolecular Chemistry
Page 10 of 10
Journal Name
ARTICLE
8
M. D. Joksović, V. Marković, Z. D. Juranić, T. Stanojković, L. S. 23 S. Tschan, A. J. Brouwer, P. R. Werkhoven, A. M. Jonker, L.
Jovanović, I. S. Damljanović, K. M. Szécsényi, N. Todorović, S.
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694, 3935.
Wagner, S. Knittel, M. N. Aminake, G. Pradel, F. Joanny, R. M. J.
View Article Online
Liskamp and B. Mordmüller, Antimicrob. Agents Chemother., 2013,
DOI: 10.1039/C5OB00364D
57, 3576.
9
(a) L. De Luca, M. Falorni, G. Giacomelli and A. Porcheddu,
Tetrahedron Lett., 1999, 40, 8701. (b) L. De Luca, G. Giacomelli, A.
Porcheddu, A. M. Spanedda and M. Falorni, Synthesis, 2000, 1295.
10 For the synthesis of optically active pyrazole containing α-amino
acids, see: (a) L. Wei and W. D. Lubell, Can. J. Chem., 2001, 79, 94.
(b) U. Ursic, D. Bevk, S. Pirc, L. Pezdirc, B. Stanovnik and J. Svete,
Synthesis, 2006, 2376.
11 For the synthesis of racemic α-amino acids bearing a pyrazole side-
chain, see: (a) A. Prešeren, J. Svete and B. Stanovnik, J. Heterocyclic
Chem., 1999, 36, 799. (b) A. de la Hoz, A. Díaz-Ortiz, M. V. Gómez,
J. A. Mayoral, A. Moreno, A. M. Sánchez-Migallón and E. Vázquez,
Tetrahedron, 2001, 57, 5421. (c) P. Calí and M. Begtrup,
Tetrahedron, 2002, 58, 1595. (d) L. Vraničar, F. Požgan, S. Polanc
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12 L. S. Fowler, D. Ellis and A. Sutherland, Org. Biomol. Chem., 2009,
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14 D. E. Rudisill and J. P. Whitten, Synthesis, 1994, 851.
15 C. M. Reid, K. N. Fanning, L. S. Fowler and A. Sutherland,
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16 For reviews of 2-pyrazoline formation from enones, see: (a) A.
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17 S. Duggineni, D. Sawant, B. Saha and B. Kundu, Tetrahedron, 2006,
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19 G. D. Fasman, Handbook of Biochemistry and Molecular Biology,
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20 The 3-nitrobiphenyl analogue 26 was found to have a emission
maximum at 434 nm, which is potentially most suitable for
application in proteins and peptides containing fluorescent
proteinogenic α-amino acids such as tyrosine and tryptophan.
However, 26 produced the weakest emission maximum of the five
pyrazole α-amino acids and so was not considered further.
21 A. J. Brouwer, T. Ceylan, T. van der Linden and R. M. J. Liskamp,
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10 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012