Synthesis of optically active α-amino acids containing pyrazolyl ring as substituent

Article abstract of DOI:10.1055/s-2000-6426

Starting from commercially available L-serine, some pyrazolyl oxazolidines have been prepared and transformed into novel chiral α-amino acids, containing a pyrazole ring, which can be regarded as building blocks for peptidomimetics.

Full text of DOI:10.1055/s-2000-6426

PAPER
1295
Synthesis of Optically Active a-Amino Acids Containing Pyrazolyl Ring as
Substituent
Lidia De Luca, Giampaolo Giacomelli,* Andrea Porcheddu, Anton Mario Spanedda, Massimo Falorni1
Dipartimento di Chimica, Università di Sassari, I-07100 Sassari, Italy
Fax +39(079)212069; E-mail: ggp@ssmain.uniss.it
Received 4 April 2000; revised 3 May 2000
tained via the Weinreb amide 2, by a previously tested
Abstract: Starting from commercially available L-serine, some
pyrazolyl oxazolidines have been prepared and transformed into
novel chiral a-amino acids, containing a pyrazole ring, which can be
regarded as building blocks for peptidomimetics.
procedure,3 in good yields (Scheme 1).
Me
N
O
O
NMM, ClCOOEt
Me3SiC CMgBr
OMe
Key words: amino acids, cycloadditions, heterocycles, hydrazones,
regioselectivity
CO2H
N
N
MeNHOMe, -15 °C
94 %
Et2O
80 %
O
Pg
Pg
2a,b
1a,b
There is currently considerable interest in the synthesis of
unusual and unnatural amino acids and their incorporation
into peptides and proteins. Peptides composed of unnatu-
ral amino acids display often intriguing secondary struc-
tures and have shown potential as medicinal agents. In
particular, they display improved metabolic stability for
proteases compared to peptides composed of natural ami-
no acids.
O
SiMe3
O
Et2NH, EtOH
NEt2
N
N
0 °C
86%
O
Pg
O
Pg
3a,b
4a,b
a; Pg = Boc, b; Pg = Cbz
In the last few years we were interested in the preparation
of unusual amino acids containing heterocyclic moi-
eties.2,3 These heterocyclic products are not only them-
selves of interest but are also valuable building blocks for
peptidomimetics, in connection with the design and syn-
thesis of drug candidates and as chiral starting materials
for many applications. Thus, there is interest in the dis-
covery and development of synthetic methodologies for
the preparation of new enantiopure a-amino acids either
through asymmetric synthesis4 or modification of natural
amino acids.5
Scheme 1
Surprisingly, compounds 3a and 4a (with Boc as N-pro-
tecting group) do not condense at all with hydroxylamine
or phenylhydrazine,7 and only the reaction with hydrazine
gave the 4-[1H-pyrazol-3(5)-yl]oxazolidine-3-carboxylic
acid tert-butyl ester (5a) in 54% yield (Scheme 2).
O
SiMe3
O
NH2NH2•H2SO4
N
N
We have previously reported a synthetic approach to a se-
ries of new chiral optically active a-amino acids contain-
ing 1,3- or 1,5-substituted pyrazolyl ring.3 Continuing our
interest in this area, we have sought to develop this meth-
od for generating and elaborating analogous functional-
ized heterocycles.
EtOH, Na2CO3, reflux
54 %
O
N
NH
Boc
Boc
5a
3a
HO
HOOC
Jones reagent
PTSA, MeOH
HN
Boc
HN
Similar to other cases, our strategy was based on the
possibility of building the amino acid derivative from
L-serine through the proper intermediate. Our previous
work in this field indicated that the best method to prepare
heterocyclic rings, such as pyrazoles and isoxazoles was
the cyclocondensation of an a-alkynyl ketone with a nu-
cleophile such as hydroxylamine or a hydrazine deriva-
tive. Moreover the reaction can be carried out in a
regioselective manner by employing trimethylsilylethy-
nyl ketones.4,5
rt
0 °C
N
NH
N NH
Boc
15 %
90 %
6
7
Scheme 2
The successive cleavage of the oxazolidine ring was
performed without affecting the N-Boc protection using
p-toluenesulfonic acid (PTSA) in anhydrous methanol at
room temperature. Under these conditions, the reaction
occurs with low conversion (15% after 24 h) affording the
amino alcohol 6. Subsequent oxidation under Jones’ con-
Therefore, for the synthesis of the target compounds
L-serine was converted into N-protected (S)-4-carboxyox-
azolidine 1,6 from which compounds 3 and 4 were ob-
Synthesis 2000, No. 9, 1295–1298 ISSN 0039-7881 © Thieme Stuttgart · New York

1296
L. De Luca et al.
PAPER
Bulb to bulb distillations were carried out with a Büchi GRK-51 ap-
paratus equipped with a vacuum controller Büchi B-168. Elemental
analyses were performed on a Perkin-Elmer 420 B analyzer. The 1H
NMR (300 MHz) and 13C NMR (75.4 MHz) Fourier transform
spectra were obtained with a Varian VXR-300 spectrometer in
CDCl3 using TMS as an intternal standard, unless otherwise speci-
fied. All reactions involving air sensitive materials were carried out
under argon; all reagents and solvents employed were reagent grade
materials purified by standard methods and distilled before use. Pe-
troleum ether used had bp 35–60 °C. As chiral starting material L-
serine of "BioChemica" grade (chemical and enantiomeric purity
>95%) purchased from Fluka Chemie AG was used. (S)-N-Boc-
(1a) and (S)-N-Cbz-4-carboxyoxazolidine (1b) were prepared ac-
cording reported procedures.6
ditions afforded (R)-N-tert-butoxycarbonylamino-(1H-
pyrazol-3(5)-yl)-acetic acid (7) in 90% yield. In a similar
manner, the N-Cbz derivatives 3b and 4b react with phe-
nylhydrazine to give compounds 8 and 9, respectively, in
good yield. In these cases, the oxazolidine ring is remark-
ably resistant to cleavage and compound 8 was only
cleaved using PTSA in methanol/water at 75 °C whereas
transformation of 9 required anhydrous methanol at the
same temperature (Scheme 3).
O
O
SiMe3
PhNHNH2.HCl
PTSA, MeOH/H2O
N N
reflux
N
N
EtOH, 75 °C
Cbz
(S)-4-(N-Methoxy-N-methylcarbamoyl)oxazolidine-3-carbox-
ylic Acid tert-Butyl Ester (2a); Typical Procedure
O
Cbz
Ph
52 %
50 %
3b
8
Under vigorous stirring at -15 °C, 4-methylmorpholine (5.1 mL,
46.3 mmol) in CH2Cl2 (20 mL) and ethyl chloroformate (8.4 mL,
88.8 mmol) in CH2Cl2 (20 mL) were added to 1a (10 g, 46.0 mmol)
in CH2Cl2 (60 mL). The mixture was stirred at -15 °C for 15 min,
then 4-methylmorpholine (10 mL, 90 mmol) and N,O-dimethylhy-
droxylamine (8.8 g, 90 mmol) were added portionwise. The result-
ing mixture was stirred at -15 °C for 1 h and at r.t. 12 h, and then
treated with H2O (100 mL). After separation of the organic layer,
the aqueous phase was extracted with EtOAc (25 mL) and the com-
bined organic layers were washed with 10% aq NaHCO3, brine, 5%
aq HCl and brine (25 mL each) in that order, and dried
(Na2SO4).The solvent was evaporated under reduced pressure and
the crude product, after purification by flash chromatography (SiO2,
EtOAc/hexane, 7:3) yielded 2a as a colorless oil (11.2 g, 94%).
HO
HOOC
KMnO4
HN
Cbz
HN
40 °C, 3h
35 %
N
N
N N
Cbz
Ph
Ph
12
10
O
N
O
N
NEt2
PhNHNH2•HCl
PTSA, MeOH
reflux
35 %
N
N
Cbz
Ph
MeOH, reflux
72 %
O
1H NMR: d = 1.45 (s, 9 H), 3.20 (br s, 3 H), 3.72 (br s, 3 H), 3.91
(m, 1 H), 4.27 (br, 1 H), 4.59-5.12 (m, 3 H).
Cbz
4b
9
13C NMR: d = 29.2, 33.5, 52.3, 64.9, 70.9, 74.0, 81.9, 156.0, 172.0.
HO
HOOC
Anal. calcd for C11H20N2O5: C, 50.76; H, 7.74; N, 10.76. Found C,
50.69; H, 7.74; N, 10.77.
Jones reagent
0 °C
15 %
HN
Cbz
Ph
HN
N
N
N
N
(S)-4-(N-Methoxy-N-methylcarbamoyl)oxazolidine-3-carbox-
ylic Acid Benzyl Ester (2b)
Cbz
Ph
Compound 2b was prepared accordingly, starting from 1b (8.8 g,
35 mmol). The crude product obtained was purified by flash chro-
matography (SiO2, EtOAc, hexane 6:4) to give pure 2b as colorless
oil (9.7 g, 94%).
11
13
Scheme 3
1H NMR (mixture of two conformers): d = 3.15 (br s, 1.8 H,), 3.23
(br s, 1.2 H), 3.48 (br s, 1.2 H), 3.79 (br s 1.8 H), 3.96 (m, 1 H), 4.32
(m, 1 H), 4.69-4.89 (m, 1 H), 4.93-5.01 (m, 1 H), 5.12 (br s, 2 H),
5.15-5.24 (br m, 1 H), 7.34 (br s, 5 H).
13C NMR: d = 33.5, 52.9, 63.9, 72.9, 81.3, 127.2,127.5,128,8,141.0,
156.0, 171.8.
Numerous methods are reported in the literature for the di-
rect conversion of primary alcohols to the corresponding
carboxylic acids, nevertheless this transformation is often
a challenge. Although we have previously observed satis-
factory results in the oxidation of analogous substrates
with Jones’ reagent, the amino alcohols 10 and 11 were
found to be particularly inert towards common oxidizing
agents. Sharpless reagent,8 pyridinium chlorochromate
(PCC) and other more recent methods9 were ineffective
and only use of KMnO4 had succeeded in obtaining the
pyrazolyl amino acid 12, while only Jones’ reagent oxi-
dized compound 11 to 13, at 0 °C with partial decomposi-
tion of the substrate.10
Anal. calcd for C14H18N2O5: C, 57.13; H, 6.16; N, 9.52. Found C,
57.11; H, 6.14; N, 9.55.
(S)-4-[3-(Trimethylsilanyl)propynoyl]oxazolidine-3-carboxylic
Acid tert-Butyl Ester (3a); Typical Procedure
To a solution of ethylmagnesium bromide (50 mmol) in anhyd Et2O
(50 mL) was added a solution of trimethylsilylacetylene (4.9 g,
50 mmol) in Et2O (20 mL) under stirring and then heated until for-
mation of a white suspension. The mixture was cooled to 0 °C and
compound 2a (10.8 g, 36.6 mmol) in anhydrous Et2O (25 mL) was
added over a period of 5 min. The mixture was stirred at r.t. for ad-
ditional 12 h, then treated with sat. aq NH4Cl. After separation of
the aqueous phase, the organic layer was washed with brine and
dried (Na2SO4). Elimination of the solvent under vacuum gave a
crude product which was purified by flash chromatography
In conclusion, a methodology for the preparation of a new
class of a-amino acids has been developed using an inex-
pensive chiral starting material. Further efforts on the pos-
sibility to carry out the synthesis of heterocyclic amino
acids through solid phase procedures are currently in
progress.
Synthesis 2000, No. 9, 1295–1298 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Optically Active a-Amino Acids Containing Pyrazolyl Ring as Substituent
1297
(EtOAc/petroleum ether, 0.2:1) to yield 3a as a pale yellow oil
(8.7 g, 80%).
1H NMR: d = 0.22 (s, 9 H), 1.43 (br s, 9 H), 4.05-4.55 (m, 3 H),
4.90 (br s,1 H), 5.01 (br s,1 H).
13C NMR: d = -0.9, 23.7, 70.6, 72.0, 73.7, 79.0, 80.4, 81.4, 153.6,
182.5.
1H NMR: d = 1.43 (br s, 9 H), 1.82-2.27 (m, 3 H), 2.26-2.13 (m, 1
H), 3.34-3.61 (m, 2 H, CH2), 4. 95 (br dd, 0.4 H, CH), 5.02 (br dd,
0.7 H, CH), 6.07 (dd, 1 H, J = 1.9 Hz), 7.44 (dd, 1 H, J = 1.9 Hz).
13C NMR: d =: 28.7, 63.5, 69.8, 80.2, 80.9, 106.8, 135.8, 145.3,
154.5.
Anal. calcd for C11H17N3O3: C, 55.22; H, 7.16; N, 17.56. Found C,
55.19; H, 7.19; N, 17.56.
Anal. calcd for C14H23NO4Si: C, 56.54; H, 7.79; N, 4.71. Found C,
56.59; H, 7.74; N, 4.70.
(R)-tert-Butoxycarbonylamino[1H-pyrazol-3(5)-yl]acetic Acid
(7)
(S)-4-[3-(Trimethylsilanyl)propynoyl]oxazolidine-3-carboxylic
Acid Benzyl Ester (3b)
p-Toluenesulfonic acid (0.35 g) was added to a solution of 5a
(0.4 g, 1.8 mmol) in anhyd MeOH (60 mL). The mixture was stirred
at r.t. for 24 h, then treated with aq sat. NaHCO3 and concentrated
in vacuo to eliminate MeOH. The residue was saturated with brine
and extracted with EtOAc. The extracts were then washed with
brine and dried (Na2SO4). Removal of the solvent under vacuum
and purification by flash chromatography (SiO2, EtOAc/petroleum
ether, 4:1) gave 6 (61 mg, 15%) as an oil, along with 0.32 g of un-
reacted 5a. Compound 6 was characterized by 1H NMR: d = 1.39 (s,
9 H), 3.15 (br s, 1 H), 3.81-3.99 (dd, 2 H, J = 1.9 Hz), 4.89 (br s, 1
H), 5.57-5.60 (br s, 1 H), 6.07 (dd, 1 H, J = 1.9 Hz), 7.48 (dd, 1 H,
J = 1.9 Hz)]. Jones’ reagent (45 mL) was added dropwise at 0 °C to
a solution of 6 (61 mg) in acetone (20 mL). The mixture was stirred
at r.t. for additional 2 h, then diluted with MeOH to destroy excess
Jones’ reagent. The organic phase was extracted with CH2Cl2, the
CH2Cl2 layer was washed with H2O and brine and extracted with aq
sat. NaHCO3. The organic phase was discarded and the aq NaHCO3
solution was treated with 10% HCl and extracted with EtOAc. The
EtOAc layer was dried (Na2SO4) and evaporated to give the pure
acid 7 (59 mg, 90%).
Compound 3b was prepared accordingly, starting from 2b (5.5 g,
18.7 mmol). The crude product obtained was purified by flash chro-
matography (SiO2, EtOAc/hexane, 6:4) to give pure 3b (4.9 g,
80%).
1H NMR (mixture of two conformers): d = 0.29 (s, 9 H), 4,22 (br s,
2 H), 4.44 (s, 0.6 H), 4.60 (s, 0.4 H), 5.00 (br s, 1 H), 5.07 (br s, 1
H), 5.16 (m, 2 H), 7.34 (m, 5 H).
13C NMR: d = -0.9, 69.6, 72.0, 73.7, 79.0, 80.4, 81.4, 127.2, 127.5,
128,8, 141.0, 153.6, 182.5
Anal. calcd for C17H21NO4Si: C, 61.60; H, 6.39; N, 4.23. Found C,
61.59; H, 6.34; N, 4.23.
(S)-4-[(E)-3-(N,N-Diethylamino)propenoyl]oxazolidine-3-car-
boxylic Acid tert-Butyl Ester (4a); Typical Procedure
A solution of 3a (1.8 g, 6.1 mmol) was added at 0 °C to a 40% aq
solution of Et2NH (12 mmol). The mixture was stirred at r.t. for 3 h,
then extracted with Et2O. After drying the Et2O layer (Na2SO4) and
removal of the solvent gave the pure enamino ketone 4a (1.6 g,
86%) as a colorless oil.
1H NMR: d = 1.14 (br t, 6 H), 1.43 (br s, 9 H), 3.23 (br q, 4 H), 3.97
(br m, 1 H), 4.09-4.40 (br m, 2 H), 4.72-5.05 (m, 2 H), 5.16 (d, 1
H, J = 12.6 Hz), 7.66 (d, 1 H, J = 12.6 Hz).
1H NMR: d = 1.35 (s, 9 H), 5.95 (s, 1 H), 6.05 (dd, 1 H, J = 1.8 Hz),
7.44 (dd, 1 H, J = 1.8 Hz), 11.4 (s, 1 H).
13C NMR: d = 28.8, 62.5, 70.6, 106.3,135.8, 144.8, 154.5, 176.0.
Anal. calcd for C10H15N3O4: C, 49.79; H, 6.27; N, 17.42. Found C,
49.81; H, 6.30; N, 17.41.
13C NMR: d = 13.8, 28.6, 46.0, 70.6, 71.9, 74.5, 80.3, 107.4, 144.0,
157.0, 191.8.
Anal. calcd for C15H26N2O4: C, 60.38; H, 8.78; N, 9.39. Found C,
60.31; H, 8.74; N, 9.35.
(S)-4-(1-Phenyl-1H-pyrazol-3-yl)oxazolidine-3-carboxylic Acid
Benzyl Ester (8); Typical Procedure
To a refluxing solution of compound 3b (2.0 g, 6.1 mmol) and phe-
nylhydrazine hydrochloride (1.2 g, 8 mmol) in EtOH was added
slowly sat. aq of Na2CO3 (1.2 g, 11 mmol). The mixture was stirred
for additional 20 h, then diluted with H2O and extracted with Et2O.
After drying the Et2O layer (Na2SO4) and removal of the solvent un-
der vacuum a viscous oil (2.2 g) was obtained. Purification by flash
chromatography (EtOAc/CH2Cl2/petroleum ether, 0.2.:0.5:1) gave
pure 8 (1.1 g, 52%).
1H NMR: d = 4.24 (br s, 1 H), 4.33 (m, 1 H), 5.08 (br m, 2 H), 5.18
(br m, 3 H), 6.41 (br d, 1 H), 7.10-7.52 (m, 8 H), 7.61-7.66 m, 2
H), 7.84 (d, 1 H, J = 1.9 Hz).
(S)-4-[(E)-3-(N,N-Diethylamino)propenoyl]oxazolidine-3-car-
boxylic Acid Benzyl Ester (4b)
Compound 4b was prepared accordingly, starting from 3b (2.0 g,
6.0 mmol). The crude product obtained was purified by flash chro-
matography (SiO2, EtOAc/EtOH, 10:1) to give pure 4b as an oil
(1.8 g, 89%).
1H NMR: d = 1.03 (br t, 3 H), 1.14 (t, 3 H, J = 7.1 Hz), 3.07 (br s, 2
H), 3.22 (q, 2 H, J = 7.1 Hz), 4.00 (m, 1 H), 4.16 (br m, 1 H), 4.40
(br m, 1 H), 4.88 (br m, 1 H), 5.10 (m, 4 H), 7.26 (br s, 5 H), 7.61
(br d, 1 H).
13C NMR: d = 13.8, 46.1, 70.0, 71.8, 74.5, 80.3, 107.2, 127.2, 127.5,
128,8, 141.0, 144.0, 157.0, 191.8.
13C NMR: d = 63.8, 69.7, 80.2, 80.9, 108.0, 118.8, 126.0, 127.2,
127.5, 128.6, 128.8, 140.0, 141.0, 151.4, 156.0.
Anal. calcd for C18H24N2O4: C, 65.04; H, 7.28; N, 8.43. Found C,
65.00; H, 7.32; N, 8.40.
Anal. calcd for C20H23N3O3: C, 68.75; H, 5.48; N, 12.03. Found C,
68.73; H, 5.48; N, 12.06.
(S)-4-[1H-Pyrazol-3(5)-yl]oxazolidine-3-carboxylic Acid tert-
Butyl Ester (5a)
(S)-4-(1-Phenyl-1H-pyrazol-5-yl)oxazolidine-3-carboxylic Acid
Benzyl Ester (9)
Compound 9 was prepared accordingly, starting from 4b (2.0 g,
6.1 mmol) in MeOH. A viscous oil (2.5 g) was obtained, which was
purified by flash chromatography (SiO2, EtOAc/CH2Cl2/petroleum
ether, 0.5:1:1) to give pure 9 (1.5 g, 72%) as an oil.
1H NMR: d = 3.87 (br s, 1H), 4.11 (br s, 1 H) 5.01-5.09 (br m, 5 H)
6.34 (d, 1H, J = 1.9 Hz), 6.98-7.55 (m, 10 H) 7.52 (d, 1 H, J = 1.9
Hz).
To a solution of 3a (1.8 g, 6 mmol) and hydrazine sulfate (1.1 g,
8 mmol) in refluxing EtOH was added slowly sat. aq Na2CO3 (1.0
g, 9 mmol). The mixture was stirred under reflux for additional 20
h, then diluted with H2O and extracted with Et2O. After drying the
Et2O layer (Na2SO4) and elimination of the solvent under vacuum a
crude product (1 g) was obtained. Purification by flash chromatog-
raphy (EtOAc/petroleum ether, 7:3) gave pure 5a (0.8 g, 54%) as an
oil.
Synthesis 2000, No. 9, 1295–1298 ISSN 0039-7881 © Thieme Stuttgart · New York

1298
L. De Luca et al.
PAPER
13C NMR: d = 57.2, 69.7, 80.5, 80.9, 108.0, 118.6, 126.0, 127.2,
0 °C for additional 4 h, then diluted with MeOH to destroy excess
Jones’ reagent. The mixture phase was extracted with EtOAc, the
combined EtOAc layers were washed with H2O and brine, and ex-
tracted with aq sat NaHCO3 solution. The organic phase was dis-
carded and the aq NaHCO3 solution was treated with 2 N HCl and
extracted with EtOAc. The organic phase was dried (Na2SO4) and
evaporated to give the pure acid 13 (0.16 g, 15%).
1H NMR: d = 5.02 (br s, 1 H), 5.16 (br s, 2 H), 6.45 (d, 1 H, J = 1.9
Hz), 7.31-7.66 (m, 10 H), 7.96 (d, 1 H, J = 1.9 Hz), 8.10 (br s, 1 H),
11.3 (s, 1 H).
127.5, 128.5, 137.3, 140.0, 141.0, 143.4, 156.6.
Anal. calcd for C20H23N3O3: C, 68.75; H, 5.48; N, 12.03. Found C,
68.77; H, 5.43; N, 11.99.
(S)-[2-Hydroxy-1-(1-phenyl-1H-pyrazol-3-yl)ethyl]carbamic
Acid Benzyl Ester (10)
p-Toluenesulfonic acid (0.92 g) was added to a solution of 8 (0.8 g,
2.2 mmol) in MeOH/H2O (1:1, 40 mL). The mixture was refluxed
for 48 h, then treated with aq sat. NaHCO3 solution and concentrat-
ed in vacuo to remove MeOH. The residue was saturated with NaCl
and extracted with EtOAc. The combined organic extracts were
then washed with brine and dried (Na2SO4). Removal of the solvent
under vacuum and purification by flash chromatography (SiO2,
EtOAc/petroleum ether, 1:1) gave 10 (0.4 g, 50%), along with
0.32 g of unreacted 8.
13C NMR: d = 55.8, 69.3, 107.9, 118.5, 125.8 127.3, 127.5, 128.7,
129.0, 136.2, 141.2, 143.2, 157.8, 176.0.
Anal. calcd for C19H17N3O4: C, 64.95; H, 4.88; N, 11.96. Found C,
64.92; H, 4.85; N, 12.05.
1H NMR: d = 3.21 (br s, 1 H), 3.95 (br d, 1 H), 4.08 (dd, 1 H, J =
12.6 Hz), 5.00 (m, 1 H), 5.15 (s, 2 H), 5.82 (br d, 1 H), 6.46 (d, 1 H,
J = 1.9 Hz), 7.27-7.40 (m, 6 H), 7.43 (t, 2 H, J = 7.2 Hz), 7.62 (d,
2 H, J = 7.2 Hz), 7.87 (d, 1 H, J = 1.9 Hz).
13C NMR: d = 56.3, 69.3, 70.8, 108.0, 118.8, 126.0, 127.2, 127.5,
128.6, 128.8, 140.0, 141.0, 151.4, 157.0.
Acknowledgement
This work was financially supported by MURST (Rome) within the
project "Chimica dei Composti Organici di Interesse Biologico Es.
Fin. 1997".
References
Anal. calcd for C19H19N3O3: C, 67.64; H, 5.68; N, 12.46. Found C,
67.63; H, 5.68; N, 12.36.
(1) Dott. Massimo Falorni died suddenly in 1999. The work
described in this paper represents his last contribution to the
research and is dedicated to his memory.
(2) Falorni, M.; Dettori, G.; Giacomelli, G. Tetrahedron:
Asymmetry 1998, 9, 1419.
(S)-[2-Hydroxy-1-(1-phenyl-1H-pyrazol-5-yl)ethyl]carbamic
Acid Benzyl Ester (11)
p-Toluenesulfonic acid (0.9 g) was added to a solution of 9 (0.8 g,
2.2 mmol) in anhyd MeOH (40 mL). The mixture was then worked
up as above. Elimination of the solvent under vacuum and purifica-
tion by flash chromatography (SiO2, EtOAc/petroleum ether, 1:1)
gave 11 (0.3 g, 35%), along with 0.12 g of unreacted 9.
Falorni, M.; Giacomelli, G.; Spanedda, A. M. Tetrahedron:
Asymmetry 1998, 9, 3039.
Falorni, M.; Giacomelli, G.; Spanu, E. Tetrahedron Lett.
1998, 39, 9241.
1H NMR: d = 1.89 (br s, 1 H), 3.97 (br d, 1 H), 4.10 (dd, 1 H, J =
12.5 Hz), 4.98 (m, 1 H), 5.14 (s, 2 H), 6.03 (br d, 1 H), 6.45 (d, 1 H,
J = 1.9 Hz), 7.29-7.40 (m, 5 H), 7.43-7.51 (m, 3 H), 7.65 (m, 2 H),
7.87 (d, 1 H, J = 1.9 Hz).
13C NMR: d = 49.3, 69.3, 71.3 108.0, 118.6, 126.0, 127.2, 127.5,
128.5, 137.3, 140.0, 141.0, 143.4, 157.3.
(3) De Luca, L.; Falorni, M.; Giacomelli, G.; Porcheddu, A.
Tetrahedron Lett. 1999, 40, 8701.
(4) Myers, A. G.; Gleason, J. L.; Yoon, T.; King, D. W. J. Am.
Chem. Soc. 1997, 119, 656, and references cited therein.
(5) Some selected examples:
Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis:
Construction of Chiral Molecules Using Amino Acids; New
York: Wiley, 1987. Zhang L.; Kauffman G. S.; Pesti J. A.; Yin
J. J. Org. Chem. 1997, 62, 6918.
Anal. calcd for C19H19N3O3: C, 67.64; H, 5.68; N, 12.46. Found C,
67.59; H, 5.63; N, 12.39.
Tamagnan G.; Neumeyer J. L.; Gao Y.; Wang S.; Kula N. S.;
Baldessarini R. J. Biorg. Med. Chem. Lett. 1997, 7, 337.
Gryko D, Jurczak J. Tetrahedron Lett. 1997, 38, 8275.
Reginato, G.; Mordini, A.; Valacchi, M.; Grandini, E. J. Org.
Chem. 1999, 64, 9211.
(R)-N-Benzyloxycarbonylamino-(1-phenyl-1H-pyrazol-3-
yl)acetic Acid (12)
A solution of KMnO4 (1.3 g) in H2O (25 ml) was added dropwise at
0 °C to a solution of 10 (2.1 g, 6.2 mmol) and Na2CO3 (0.1 g) in H2O
(14 mL). The mixture was stirred at r.t. for 12 h, then stirred at 45 °C
for additional 1.5 h. The mixture was filtered, extracted with Et2O,
and the aqueous layer was acidified with 10% HCl. The product was
extracted with Et2O, the Et2O phase was washed with H2O and brine
and dried (Na2SO4). Removal of the solvent gave the pure acid 12
(0.8 g, 35%).
(6) Falorni, M.; Conti, S.; Giacomelli, G.; Cossu, S.; Soccolini, F.
Tetrahedron: Asymmetry 1995, 6, 287.
(7) The reactions gave a complex mixture of compounds, from
which the target products were isolated only in traces.
(8) Eberard, A.; Westheimer, F. H. J. Am. Chem. Soc. 1965, 87,
253.
(9) Zhao, M.; Li, J.; Song, Z.; Desmond, R.; Tschaen, D. M.;
Grabowski, E. J. J.; Reider, P. Tetrahedron Lett. 1998, 39,
5323.
(10) The Jones' reagent was known to oxidize N-protected amino
alcohols without any evidence of racemization.4,5 Compound
12 was found to be 95% ee by chiral GC (Chirasil-L-val
column) after conversion to the corresponding methyl ester
with excess MeI in the presence of NaHCO3.
1H NMR: d = 5.02 (br s, 1 H), 5.16 (br s, 2 H), 6.45 (d, 1 H, J = 1.9
Hz), 7.31-7.66 (m, 10 H), 7.96 (d, 1 H, J = 1.9 Hz) 8.10 (br s, 1 H),
11.3 (s, 1 H).
13C NMR: d = 62.3, 69.1, 107.5, 118.3, 126.0, 127.0, 127.2, 128.7,
128.8, 139.2, 140.2, 151.6, 157.8, 176.2.
Anal. calcd for C19H17N3O4: C, 64.95; H, 4.88; N, 11.96. Found C,
64.88; H, 4.88; N, 12.01.
(R)-N-Benzyloxycarbonylamino-(1-phenyl-1H-pyrazol-5-
yl)acetic Acid (13)
Jones’ reagent (3 mL) was added dropwise at 0 °C to a solution of
11 (1.0 g, 3.0 mmol) in acetone (20 mL). The mixture was stirred at
Article Identifier:
1437-210X,E;2000,0,09,1295,1298,ftx,en;Z02500SS.pdf
Synthesis 2000, No. 9, 1295–1298 ISSN 0039-7881 © Thieme Stuttgart · New York