Synthesis of chiral pyrazoles and isoxazoles as constrained amino acids

Article abstract of DOI:10.1016/S0957-4166(98)00305-X

A stereospecific syntheses of optically active pyrazoles and isoxazoles from L-proline is described. The procedure presented is based on readily available materials and can be used for preparing new conformationally restricted pyrazole-containing amino ac

Full text of DOI:10.1016/S0957-4166(98)00305-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3039–3046
Synthesis of chiral pyrazoles and isoxazoles as constrained amino
acids
Massimo Falorni, Giampaolo Giacomelli ∗ and Anton Mario Spanedda
Dipartimento di Chimica, Università di Sassari, via Vienna 2, I-07100 Sassari, Italy
Received 26 June 1998; accepted 30 July 1998
Abstract
A stereospecific syntheses of optically active pyrazoles and isoxazoles from L-proline is described. The
procedure presented is based on readily available materials and can be used for preparing new conformationally
restricted pyrazole-containing amino acids. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Nonproteinogenic amino acids play an important role in pharmaceutical applications; from this point
of view, heteroaryl substituted α-amino acids have been recently considered.1 A novel and important
class of amino acid derived heterocycles is represented by isoxazoles and isothiazoles. During studies
on ligands which activate neuronal nicotinic acetylcholine receptors for the palliative treatment for
the symptoms of memory loss,2 a series of novel 3,5-disubstituted isoxazoles and isothiazoles were
prepared starting from L-proline, by reacting N-Boc-protected-20-pyrrolidinyl acetylene with a nitrile
oxide generated in situ from a nitro precursor.3,4 The reaction is very convenient but suffers due to the
lack of availability of the nitro derivative, moreover the reaction does not occur with nitromethane.
Recently we have become interested in the field of NMDA antagonists;5 in this context the possibility
of preparing amino acids containing heterocycles appeared very attractive.
A reliable retrosynthetic analysis for the above compounds suggested the cyclocondensation of an α-
acetylenic ketone with a nucleophile such as hydrazine and hydroxylamine derivatives. The reaction is
not regioselective in the original procedure,6 but more recent modifications have shown that the method
can be conducted in a highly regioselective manner using silylacetylenic ketones, at least with simple
∗
Corresponding author. E-mail: ggp@ssmain.uniss.it
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00305-X
tetasy 2454 Article

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substrates.7 Therefore, in order to acquire more information about the possibility of using a different
method from that reported3,4 to achieve optically active heterocycle-containing amino acids, we have
tested the procedure by using L-proline as the starting amino acid. Here we wish to report the synthesis
of optically active 2-pyrazolyl- and 2-isoxazolyl-pyrrolidine derivatives 1–5.
2. Results and discussion
The preparation of the compounds 1–4 began with the conversion of (S)-N-tert-butoxycarbonyl
proline into the corresponding Weinreb prolinamide 6 through reaction with 2 equiv. of N,O-
dimethylhydroxylamine,8 after treatment with ethyl chloroformate (Scheme 1). The synthesis
of (S)-1-trimethylsilyl-3-(20 -N0-tert-butoxycarbonylpirrolidinyl)propin-3-one 7 was performed by
reacting (S)-N-tert-butoxycarbonyl-(N0 -methoxy-N0-methyl)prolinamide 6 with trimethylsilylethynyl
magnesium bromide. The treatment with Et2NH provided an efficient and quantitative transformation to
(S)-(E)-1-N,N-diethylamino-3-(20 -N0-tert-butoxycarbonylpyrrolidinyl)-propen-3-one 8.
Scheme 1.
The cyclocondensations were carried out as generally described.7 The acetylenic ketone 7 was
refluxed with an ethanolic solution of 1.5 equiv. of hydrazine sulfate and then treated with a saturated
solution of Na2CO3 and (20S)-3(5)-(20-N-tert-butoxycarbonyl-pyrrolidinyl)pyrazole 9 was isolated in
50% yield after flash-chromatography purification. Using similar conditions, (20S)-1-phenyl-3-(20 -N-
tert-butoxycarbonylpyrrolidinyl)pyrazole 10 was obtained (Scheme 2). The isomeric (20S)-1-phenyl-3-
(20-N-tert-butoxycarbonylpyrrolidinyl)pyrazole 11 was recovered in 50% yield by refluxing an ethanolic
solution of phenylhydrazine with the enamino ketone 8.
Unfortunately, problems were encountered in the reaction of compounds 7 and 8 with hydroxylamine.
Firstly, no isoxazole was formed from the compounds 7, under various reaction conditions. Secondly,
the formation of (20S)-5-(20-N-tert-butoxycarbonyl-pyrrolidinyl)isoxazole 12 occurred to a poor extent
(35% yield) and all attempts to increase the yield were unsuccessful.
In all cases no trace of the corresponding regioisomer was found in the recovered products. The
removal of the protective group by trifluoroacetic acid afforded the compounds 1–4, which were

M. Falorni et al. / Tetrahedron: Asymmetry 9 (1998) 3039–3046
3041
Scheme 2.
characterized by NMR analysis. The stereochemical course of the cyclocondensation was evaluated by
1H NMR analysis of the diastereoisomeric Mosher amide, prepared by reaction of (R)-(−)-α-methoxy-α-
(trifluoromethyl)phenylacetic acid chloride (MPTACl) with (20S)-1-phenyl-5-(20 -pyrrolidinyl)pyrazole
3. The two diastereomers were found to be clearly distinguishable and consisted of a 95:5 mixture. From
these data, an enantiomeric purity of about 90% could be calculated, demonstrating that a small amount
of racemization accompanies the cyclocondensation reaction.
Thus, the synthetic protocol we have chosen for preparing chiral optically active heterocyclic systems
from L-proline seems to be convenient and versatile, at least for pyrazole substrates. Therefore, in order to
obtain information about the applicability of the reaction to more complex systems, we have undertaken
the preparation of (20S)-3(5)-formyl-5(3)-(20 -pyrrolidinyl)pyrazole (5) as a useful intermediate for the
synthesis of new optically active conformationally restricted amino acids, such as 3(5)-alkylamino-5(3)-
carboxy pyrazoles, as a valuable tool in the design of peptidomimetics.9 Thus, a sample of compound
6 was treated with the Grignard reagent from 3,3-dimethoxy-1-propyne in THF to give compound 13;
the next reaction with an ethanolic solution of hydrazine gave (20S)-3(5)-diethoxymethyl-5(3)-(20 -N-
tert-butoxycarbonylpyrrolidinyl)pyrazole 14 in good yield (55%) after purification (Scheme 3). The
1
deprotection of 14 furnished a sample of compound 5, the structure of which was confirmed by H
NMR analysis.10

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M. Falorni et al. / Tetrahedron: Asymmetry 9 (1998) 3039–3046
Scheme 3.
3. Experimental section
Melting and boiling points are uncorrected. Bulb to bulb distillations were carried out with a Büchi
GRK-51 apparatus equipped with a vacuum controller Büchi B-168. Melting points were determined
on a microscope Leitz LABORLUX S equipped with Leitz Microscope Heating Stage 350 and are
uncorrected. Elemental analyses were performed on a Perkin–Elmer 420 B analyzer. Optical rotations
1
were measured with a Perkin–Elmer 241 automatic polarimeter in a 1 dm tube. The H NMR (300
MHz), 13C NMR (75.4 MHz) and 19F NMR (282 MHz) Fourier transform spectra were obtained
with a Varian VXR-300 spectrometer on CDCl3 solutions (unless otherwise specified). All reactions
involving air sensitive materials were carried out under an argon atmosphere; all reagents and solvents
employed were reagent grade materials purified by standard methods and distilled before use. As chiral
starting material L-proline of ‘BioChemica’ grade (chemical and enantiomeric purity >99%) purchased
from Fluka Chemie AG was used. L-N-Boc-Proline was prepared according to reported procedures.
Satisfactory microanalyses were obtained for all unknown compounds: Cꢀ0.32%, Hꢀ0.40, Nꢀ0.16.
3.1. (S)-N-tert-Butoxycarbonyl-(N0 -methoxy-N0-methyl)prolinamide, 6
Under vigorous stirring and at −15°C, 4-methylmorpholine (5.1 mL, 46.3 mmol) in CH2Cl2 (20 mL)
and ethylchloroformate (8.4 mL, 88.8 mmol) in CH2Cl2 (20 mL) were added to (S)-N-Boc-proline (10
g, 46.3 mmol) in CH2Cl2 (60 mL). The reaction mixture was stirred at −15°C for 15 min, then 4-
methylmorpholine (10 mL, 90 mmol) and N,O-dimethylhydroxylamine (8.8 g, 90 mmol) were added
portionwise. The resulting mixture was stirred at −15°C for 1 h, 12 h at rt, then treated with water (100
mL). After separation of the organic layer, the aqueous phase was extracted with EtOAc (25 mL) and
washed with 10% aq. NaHCO3, sat. aq. NaCl, 5% aq. HCl and sat. aq. NaCl (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:CH2Cl2=1:1) yielded 6, as a colourless oil (9.5 g,
80%); 1H NMR δ: (mixture of two conformers) 1.38 (s, 4.5H, Boc), 1.43 (s, 4.5H, Boc), 1.70–1.89 (m,
2H), 1.89–2.03 (m, 1H), 2.15 (m, 1H), 3.16 (s, 3H, N–CH3), 3.32–3.48 (m, 1H), 3.48–3.61 (m, 1H),
3.69 (s, 1.5H, O–CH3), 3.75 (s, 1.5H, O–CH3), 4.57 (dd, 0.5H, CH), 4.69 (dd, 0.5H, CH); 13C NMR δ:
(mixture of two conformers) 168.3, 143.6, 74.0, 62.4, 61.5, 57.2, 56,8, 47.0, 32.8, 28.7, 23.7.

M. Falorni et al. / Tetrahedron: Asymmetry 9 (1998) 3039–3046
3043
3.2. (S)-1-Trimethylsilyl-3-(20 -N-tert-butoxycarbonylpyrrolidinyl)propyn-3-one, 7
To a solution of 50 mmol of ethyl magnesium bromide in 50 mL of anhydrous diethyl ether,
trimethylsilyl acetylene (4.9 g, 50 mmol) in 20 mL of ether was slowly added under stirring and then
heated until formation of a white suspension. The mixture was then kept at 0°C and compound 6 (9.5 g,
36.6 mmol) in 25 mL of anhydrous ether was added over a period of 5 min. The solution was stirred at
rt for an additional 12 h, then treated with saturated aq. NH4Cl. After separation of the organic layer, the
aqueous phase was washed with brine and dried (Na2SO4). Elimination of the solvent under vacuum gave
a crude product which was purified by flash chromatography (EtOAc:petroleum ether:CH2Cl2=1:3:6) to
yield 7 as a yellow crystalline solid (mp 76–77°C, 5.5 g, 60%), [α]25 −74.9 (c 7, CH2Cl2); 1H NMR
D
(mixture of two conformers) 0.22 (s, 9H, –SiMe3), 1.41 (s, 6.3H, Boc), 1.46 (s, 2.7H, Boc), 1.82–2.03
(m, 3H), 2.10–2.30 (m, 1H), 3.43–3.55 (m, 2H), 4.21 (dd, 0.7H, CH), 4.40 (dd, 0.3H, CH); 13C NMR δ:
(mixture of two conformers) 182.5, 153.6, 90.3, 80.4, 73.7, 66.6, 66.4, 46.8, 46.5, 30.2, 28.4, 23.7, −0.9.
3.3. (S)-(E)-1-N,N-Diethylamino-3-(20 -N-tert-butoxycarbonylpyrrolidinyl)propen-3-one, 8
A solution of 7 (1.8 g, 6.1 mmol) was added at 0°C to a 40% aq. solution of Et2NH (12 mmol).
The reaction mixture was stirred at room temperature for 3 h, then extracted with diethyl ether. After
drying (Na2SO4) and removal of the solvent, the oil residue was purified by flash chromatography
(EtOAc:acetone:petroleum ether=60:25:15) to give the enamino ketone 8 (1.7 g, 96%) as a pale yellow
1
solid (mp 82–83°C, 5.5 g, 61%), [α]25 −104 (c 3, CH2Cl2); H NMR (mixture of two conformers)
D
1.07–1.29 (broad signal, 6H), 1.39 (s, 6.3H, Boc), 1.43 (s, 2.7H, Boc), 1.78–2.25 (m, 4H), 3.12–3.34
(broad signal, 4H, N–CH2), 3.35–3.57 (m, 2H), 4. 15 (m, 0.7H, CH), 4.30 (dd, 0.3H, CH), 5.13 (t like,
1H, _CH, J=12.5), 7.65 (d, 1H, _CH, J=12.5); 13C NMR δ: (mixture of two conformers) 191.9, 157.2,
144.0, 107.5, 74.4, 67.8, 47.4, 41.2, 28.9, 24.3, 20.8, 13.2.
3.4. (S)-1,1-Diethoxy-4-(20 -N-tert-butoxycarbonylpyrrolidinyl)but-2-yn-4-one, 13
To a solution of 4 mmol of ethyl magnesium bromide in 10 mL of anhydrous diethyl ether, 3,3-
diethoxy-1-propyne (0.58 g, 4.5 mmol) in 20 mL of ether was slowly added under stirring and then
heated until formation of a white suspension. The mixture was then kept at 0°C and compound 6 (1.0
g, 3.9 mmol) in 25 mL of anhydrous ether was added. The solution was stirred at rt for additional 20
h, then treated with saturated aq. NH4Cl. After separation of the organic layer, the aqueous phase was
washed with brine and dried (Na2SO4). Elimination of the solvent under vacuum gave a crude product
which was purified by flash chromatography (EtOAc:petroleum ether:CH2Cl2=1:3:6) to yield 13 as a pale
brown oil (0.3 g, 24%), [α]25 −51.5 (c 3, CH2Cl2); 1H NMR (mixture of two conformers) 1.15 (t, 6H,
D
CH3–CH2), 1.33 (s, 6.3H, Boc), 1.38 (s, 2.7H, Boc), 1.74–2.01 (m, 3H), 2.07–2.24 (m, 1H), 3.42–3.58
(m, 4H, CH3–CH2), 3.57–3.71 (m, 2H, CH2), 4.18 (dd, 0.7H, CH), 4.32 (dd, 0.3H, CH), 5.30 (s, 1H,
O–CH–O); 13C NMR δ: (mixture of two conformers) 182.0, 131.8, 91.2, 87.7, 80.7, 80.2, 66.9, 66.8,
66.2, 61.7, 46.8, 30.3, 28.4, 23.9, 24.5, 15.2.
3.5. (20S)-3(5)-(20-N-tert-Butoxycarbonylpyrrolidinyl)pyrazole, 9
To a solution of compound 7 (1.8 g, 6 mmol) and hydrazine sulphate (1.1 g, 8 mmol) in refluxing
ethanol, a saturated aq. solution of Na2CO3 (1.0 g, 9 mmol) was added slowly. The mixture was stirred
under reflux for an additional 20 h, then diluted with water and extracted with ether. After drying

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M. Falorni et al. / Tetrahedron: Asymmetry 9 (1998) 3039–3046
(Na2SO4) and elimination of the solvent under vacuum a crude product (1 g) was obtained: purification
by flash chromatography (EtOAc:CH2Cl2:acetone=1:2:1) gave pure 9 (0.7 g, 50%), [α]25 −80.6 (c 4,
D
CH2Cl2); 1H NMR (mixture of two conformers) 1.28 (s, 4H, Boc), 1.44 (s, 5H, Boc), 1.82–2.27 (m, 3H),
2.26–2.13 (m, 1H), 3.34–3.61 (m, 2H, CH2), 4. 95 (broad dd, 0.4H, CH), 5.02 (broad dd, 0.7H, CH), 6.07
(dd, 1H), 7.44 (dd, 1H); 13C NMR δ: 176.4, 153.8, 145.3, 116.8, 69.8, 55.0, 46.6, 31.1, 28.7, 21.3.
3.6. (20S)-1-Phenyl-3-(20-N-tert-butoxycarbonylpyrrolidinyl)pyrazole, 10
To a solution of compound 7 (1.8 g, 6.1 mmol) and phenylhydrazine hydrochloride (1.2 g, 8 mmol)
in ethanol, kept at reflux, a saturated aq. solution of Na2CO3 (1.2 g, 11 mmol) was added slowly. The
mixture was stirred for an additional 20 h, then diluted with water and extracted with ether. After drying
(Na2SO4) and elimination of the solvent under vacuum a crude viscous oil (2 g) was obtained: purification
by flash chromatography (EtOAc:CH2Cl2:petroleum ether=1.5:1:1) gave pure 10 (0.8 g, 42%), [α]25
D
1
−67.9 (c 4, CH2Cl2); H NMR (mixture of two conformers) 1.26 (s, 6H, Boc), 1.46 (s, 3H, Boc),
1.85–2.03 (m, 2H), 2.13–2.27 (m, 2H), 3.43–3.61 (m, 2H), 4. 95 (broad dd, 0.6H, CH), 5.03 (broad
dd, 0.4H, CH), 6.28 (d, 1H), 7.22 (t, 1H), 7.39 (t, 2H), 7.64 (d, 2H), 7.79 (d, 1H); 13C NMR δ: 154.5,
140.1, 129.2, 126.8, 125.9, 118.7, 113.7, 105.8, 79.1, 55.6, 46.6, 33.8, 28.2, 23.3.
3.7. (20S)-1-Phenyl-5-(20-N-tert-butoxycarbonylpyrrolidinyl)pyrazole, 11
A solution of compound 8 (0.5 g, 1.7 mmol) and phenylhydrazine hydrochloride (0.3 g, 2.0 mmol)
in methanol was kept at reflux for 7 h, then diluted with water and extracted with ether. After drying
(Na2SO4) and elimination of the solvent under vacuum a crude viscous oil (0.6 g) was obtained:
purification by flash chromatography (EtOAc:CH2Cl2:petroleum ether=9:3:10) gave pure 11 (0.2 g, 38%)
as a crystalline solid, mp 110–112°C, [α]25D +9.5 (c 2, CH2Cl2); 1H NMR (mixture of two conformers)
1.24 (s, 6H, Boc), 1.44 (s, 3H, Boc), 1.77–2.03 (m, 3H), 2.01–2.21 (m, 1H), 3.30–3.68 (m, 2H), 4.90
(broad dd, 0.6H, CH), 5.14 (broad dd, 0.4H, CH), 6.15 (s, 1H), 7.22–7.51 (m, 5H), 7.64 (s, 1H); 13C
NMR δ: 154.5, 139.5, 129.1, 128.1, 125.7, 106.8, 103.9, 90.3, 79.7, 53.5, 46.4, 33.9, 28.2, 22.8.
3.8. (20S)-5-(20-N-tert-Butoxycarbonylpyrrolidinyl)isoxazole, 12
A solution of compound 8 (0.7 g, 2.4 mmol) and hydroxylamine hydrochloride (0.18 g, 2.6 mmol)
in methanol was kept at reflux for 7 h, then diluted with water and extracted with ether. After drying
(Na2SO4) and elimination of the solvent under vacuum a crude yellow oil (0.5 g) was obtained:
purification by flash chromatography (EtOAc:petroleum ether=7:3) gave pure 12 (0.2 g, 35%), [α]25
D
1
−105 (c 5, CH2Cl2); H NMR (mixture of two conformers) 1.21 (s, 6H, Boc), 1.32 (s, 3H, Boc),
1.77–2.03 (m, 3H), 2.01–2.21 (m, 1H), 3.30–3.68 (m, 2H), 4.90 (broad dd, 0.6H, CH), 5.14 (broad dd,
0.4H, CH), 6.15 (s, 1H), 7.22–7.51 (m, 5H), 7.64 (s, 1H); 13C NMR δ: 154.5, 139.5, 129.1, 128.1, 125.7,
106.8, 103.9, 90.3, 79.7, 53.5, 46.4, 33.9, 28.2, 22.8.
3.9. (20S)-3(5)-(20-N-tert-Butoxycarbonyl-pyrrolidinyl)-5(3)-(1,1-diethoxymethyl) pyrazole, 14
The compound 14 was prepared following the procedure described for 9, starting from 13 (0.27 g, 0.83
mmol). The crude product obtained was purified by flash chromatography (EtOAc:CH2Cl2=2:1) to give
pure 14 (mp 159–161°C, 0.2 g, 78%), [α]25D −158 (c 3, CH2Cl2); 1H NMR (mixture of two conformers)
1.12 (t, 6H, CH3), 1.22 (s, 6H, Boc), 1.35 (s, 3H, Boc), 1.72–1.98 (m, 3H), 2.02–2.17 (m, 1H), 3.24–3.34

M. Falorni et al. / Tetrahedron: Asymmetry 9 (1998) 3039–3046
3045
(m, 1H), 3.38–3.64 (m, 5H), 4. 81 (dd, 0.4H, CH), 4.88 (dd, 0.7H, CH), 5.49 (d, 1H), 6.06 (d, 1H); 13C
NMR δ: 176.4, 153.8, 101.8, 98.7, 81.1, 55.8, 52.3, 47.3, 30.4, 28.8, 24.9, 15.2.
3.10. Deprotection of compounds 1–5: general procedure
(a): To a solution of 0.57 mmol of Boc-protected substrate (1–5) in 5 mL of CH2Cl2, 2 mL of
trifluoroacetic acid were added at 0°C. The mixture was stirred for an additional hour at 0°C and then
concentrated in vacuo. The residue was washed with saturated NaHCO3 and continuously extracted
with CH2Cl2. After solvent evaporation, the residue was purified by flash chromatography to give the
following pure compound.
3.10.1. (20S)-3(5)-(20-Pyrrolidinyl)pyrazole, 1
1
37% Yield, [α]25 −21.9 (c 1, CHCl3); H NMR 1.81–2.18 (m, 3H), 2.26–2.46 (m, 1H), 3.26–3.52
D
(m, 2H, CH2), 4. 80 (m, 1H, CH), 6.21 (d, 1H), 6.92 (broad s, 2H, NH), 7.54 (d, 1H); 13C NMR δ: 144.3,
126.8, 105.3, 57.2, 44.6, 32.2, 22.1.
3.10.2. (20S)-1-Phenyl-3-(20-pyrrolidinyl)pyrazole, 2
57% Yield, [α]25 −31.1 (c 2, CH2Cl2); 1H NMR 2.10 (m, 2H), 2.29 (m, 1H), 2.41 (m, 1H), 3.48 (m,
D
2H), 4.82 (dd, 1H, CH), 6.60 (d, 1H, J=2.5), 6.78 (broad s, 1H, NH), 7.27 (t, 1H), 7.43 (t, 2H), 7.65 (d,
2H), 7.83 (d, 1H, J=2.5); 13C NMR δ: 140.1, 129.2, 126.8, 125.3, 108.6, 113.7, 105.8, 57.6, 44.6, 32.2,
23.1.
3.10.3. (20S)-1-Phenyl-5-(20-pyrrolidinyl)pyrazole, 3
Mp 144°C, 91% yield, [α]25 +39.1 (c 2, CH2Cl2); 1H NMR 1.94–2.35 (m, 4H), 3.18 (m, 1H, CH2),
D
3.37 (m, 1H, CH2), 4.56 (dd, 1H, CH), 4.96 (broad s, 1H, NH), 6.68 (d, 1H, J=2.5), 7.38 (t, 2H), 7.44
(t, 2H), 7.46 (d, 1H), 7.63 (d, 1H, J=2.5); 13C NMR δ: 140.8, 139.8, 137.8, 129.9, 126.2, 118.9, 106.6,
54.6, 45.4, 33.1, 23.9.
(b): A sample of product (5 mmol) was dissolved in 5 mL of EtOAc; to this solution 4.5 N HCl in
EtOAc (17 mL) was rapidly added under magnetic stirring and slowly a precipitate was formed. After
30 min the solvent was removed in vacuo (0.01 mbar) affording the pure compound as hydrochloride,
which was purified by washing with petroleum ether. The pure compound can be obtained by washing
the hydrochloride with saturated NaHCO3 and continuously extracting with CH2Cl2.
3.10.4. (20S)-5-(20-Pyrrolidinyl)isoxazole, 4
From (a): 31% yield; 1H NMR 1.80 (m, 3H), 2.10 (m, 1H), 3.01 (m, 2H), 4.29 (dd, 1H, CH), 6.04 (s,
1
1H), 8.06 (s, 1H): from (b) as hydrochloride (mp 137–139°C, 82% yield), [α]25 +5.8 (c 2, H2O); H
D
NMR (D2O) 2.19 (m, 3H), 2.54 (m, 1H), 3.48 (m, 2H), 5.01 (dd, 1H, CH), 6.64 (s, 1H), 8.46 (s, 1H); 13
C
NMR δ: 162.2, 148.5, 101.1, 50.8, 42.8, 25.6, 20.1.
3.10.5. (20S)-3(5)-Formyl-5(3)-(20 -pyrrolidinyl)pyrazole, 5
From (a): 18% yield; 1H NMR (DMSO-d6) 1.98–2.09 (m, 3H), 2.38–2.47 (m, 1H), 3.46–3.57 (m, 2H),
5.14 (dd, 1H, CH), 5.79 (s, 1H), 8.34 (s, 1H, CHO): from (b) as hydrochloride (mp 180°C (dec), 86%
yield) [α]25 +7.4 (c 0.5, H2O); 1H NMR (D2O) 2.22–2.45 (m, 3H), 2.54–2.72 (m, 1H), 3.58 (m, 2H),
D
4.96 (dd, 1H, CH), 6.90 (s, 1H), 9.93 (s, 1H); 13C NMR δ: 182.0, 146.5, 135.7, 105.2, 53.6, 42.4, 26.6,
20.1.

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3.11. Determination of the ee
A sample of 3 (70 mg, 0.33 mmol) and distilled (+)-MPTACl (0.1 g, 0.4 mmol) were mixed with
CH2Cl2 and dry pyridine (1 mL) at 0°C and allowed to stand for 48 h at rt. Water was added and the
mixture extracted with diethyl ether. The ethereal phase was washed successively with sat. aq. Na2CO3,
water and dried (Na2SO4). After removal of the solvent in vacuo the residual 1-phenyl-5-[10-(α-methoxy-
α-trifluoromethylphenylacetyl)-20 -pyrrolidinyl]pyrazole was analyzed by 1H NMR and 19F NMR.
Acknowledgements
We thank the MURST, Roma, for the financial support in the project 40%, Es. Fin 97, Sostanze
Organiche Naturali.
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10. The aldehyde can be stored under argon or as hydrochloride. When in solvent, the free aldehyde undergoes slow
decomposition.