Asymmetric synthesis of 3-substituted pyrrolidones via α-alkylation of a chiral non-racemic γ-lactam

Article abstract of DOI:10.1016/S0957-4166(98)00024-X

3-Alkyl pyrrolidones 9 were synthesized in good yield and high diastereoselectivity by α-alkylation of the new chiral non-racemic lactam 8 derived from (R)-(-)-phenylglycinol. After debenzylation and introduction of an electron-withdrawing group, 3-methylpyrrolidone 10 is easily hydrolyzed in a basic medium to produce γ-aminobutyric acid (GABA) analogue 13.

Full text of DOI:10.1016/S0957-4166(98)00024-X

Pergamon
Tetrahedron: Asymmetry 9 (1998) 797–804
Asymmetric synthesis of 3-substituted pyrrolidones via
α-alkylation of a chiral non-racemic γ-lactam
Isabelle Baussanne, Catherine Travers and Jacques Royer ∗
Institut de Chimie des Substances Naturelles, CNRS, 1 Avenue de la Terrasse, F-91198 Gif-sur-Yvette, France
Received 5 January 1998; accepted 20 January 1998
Abstract
3-Alkyl pyrrolidones 9 were synthesized in good yield and high diastereoselectivity by α-alkylation of the
new chiral non-racemic lactam 8 derived from (R)-(−)-phenylglycinol. After debenzylation and introduction of
an electron-withdrawing group, 3-methylpyrrolidone 10 is easily hydrolyzed in a basic medium to produce γ-
aminobutyric acid (GABA) analogue 13. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Numerous biological compounds possess a pyrrolidine ring as the main structure or as a structural
subunit.1,2 Enantiomerically pure pyrrolidines and pyrrolidinones can also be used as chiral auxiliaries,3
synthetic intermediates4 or chiral ligands5 in synthesis. Likewise, pyrrolidones are useful precursors of
γ-aminobutyric acid (GABA) analogues.6 In all cases, the heterocycle is substituted in various positions
with precise configurations. There is a clear interest in developing a method for the construction of
differently substituted pyrrolidines with control of the diastereoselectivity.
In this respect, we reported three years ago the one-step preparation of the lactam 17 from (R)-
(−)-phenylglycinol and dimethoxydihydrofuran and envisaged its use as a new chiral starting material
(Scheme 1).
Scheme 1.
∗
Corresponding author. Fax: (33) 01 69 07 72 47; e-mail: royer@icsn.cnrs-gif.fr
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00024-X

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Indeed the lactam 1 was easily di-alkylated α to the carbonyl group7 in high yield and high
diastereomeric excess (Scheme 2). Furthermore, 5-substituted pyrrolidones 5 were obtained with com-
plete threo selectivity through the condensation8 of a chiral silyloxypyrrole 4 (derived from 1) with
achiral aldehydes (Scheme 2). This methodology was applied in the synthesis of an aza-muricatacin. 9
Scheme 2.
Diastereoselective alkylations at C-3 of a pyrrolidine ring have already been reported, mainly starting
from pyroglutamic acid.10 Indeed, methods for the preparation of enantiomerically pure pyrrolidines
and γ-lactams substituted exclusively at the C-3 position are rare.11–13 The bicyclic lactam methodology
developed by Meyers et al.12 gave moderate diastereoselectivity for mono-substitution. Nevertheless, a
new method using alkylation of N-dialkylaminolactams has been recently reported by Enders13 to give
good results.
With this objective, we first envisaged the reduction of α-monosubstituted α,β-unsaturated γ-lactams
7 synthesized by alkylation of the lactam 1 or preferably the in situ reduction of the supposed intermediate
6 (Scheme 3). However, under all the experimental conditions investigated, pyrrolidone 9 was obtained
in an almost equimolar mixture of diastereomers. Thus, on the observation of the recently reported
alkylation of an analogous δ-lactam,14 we decided to transform 1 into the saturated γ-lactam 8 before
carrying out the alkylation study (Scheme 3).
Scheme 3.
2. Results and discussion
After reduction of lactam 1 under catalytic hydrogenation conditions, the alkylation of 8 was investi-
gated (Table 1). Following our previous studies with the α,β-unsaturated lactam 1, LDA was first studied

I. Baussanne et al. / Tetrahedron: Asymmetry 9 (1998) 797–804
799
Table 1
as the base but was not found to be the best reagent for deprotonation of 8. The yields remained low
in the presence of a cosolvent (HMPA) or a salt (LiBr). As observed in the δ-lactam series,14 the best
results were obtained using sec-butyllithium. Upon deprotonation with two equivalents of base in THF at
−78°C for 20 min, the intermediate enolate was trapped with different alkyl halides. Lactams 9a–d were
obtained in good yields and diastereomeric purities (Table 1). The diastereoselectivities were determined
by GC–MS or 1H and 13C NMR analyses on the crude reaction mixtures.
The major diastereomer resulted from a preferential attack of the electrophile on the si face of the
enolate, as had been observed previously in the di-alkylation of 1.7 This was proved after determination
of the absolute configuration of compound 9a by chemical correlation (vide infra).
While the diastereoselectivity of this alkylation process was of the same order as that reported by
Enders,13 it remained lower than that observed in the δ-lactam or the acyclic amide series for the same
chiral auxiliary and very similar experimental conditions.14 This difference could not be explained. The
origin of the diastereoselectivity has been examined using models depicted in Scheme 4. Due to a high
pyramidalization of the nitrogen in amide enolate,15,12a the N-lone pair becomes a very good electron
donor allowing chelation of the lithium ion. This chelation process had been previously invoked to
explain alkylation results with amide enolates.13,14b,16 Two diastereomeric chelated enolates A and B
can be proposed (Scheme 4). On account of the stereoelectronic effect,17 one can expect a preferred
attack of the electrophile anti to the nitrogen lone pair. In each case, A and B, the phenyl group lies on
this preferred face of the enolate, but is more remote from the double bond in A than in B. This could
explain the observed majority si attack of the electrophile. Thus, both steric and stereoelectronic effects
can explain the formation of 9 as the major compound.
Scheme 4.
The transformation of alkylated lactams 9 to 2-substituted GABA analogues was exemplified by the
synthesis of (2S)-2-methyl-4-(tert-butyloxycarbonylamino)butyric acid 13 (Scheme 5). This transforma-
tion was achieved by debenzylation of lactam 9a using lithium in liquid ammonia, followed by hydrolysis

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I. Baussanne et al. / Tetrahedron: Asymmetry 9 (1998) 797–804
of the resultant lactam 10 in a strongly acidic medium at reflux.13,18 We preferred the introduction of an
electron-withdrawing group on the nitrogen atom in order to facilitate the amide bond cleavage in basic
media19 in order to access the GABA analogues under milder conditions. Thus formation of the N-Boc
derivative 12 was followed by hydrolysis with lithium hydroxide in THF using Grieco’s conditions20 to
produce the GABA analogue 13 in 76% yield (Scheme 5). Furthermore, these transformations permitted
the assignment of the absolute configuration of alkylated lactam 9a to be 3S by comparison of specific
rotations of lactam 10 and amino acid 13 with those reported in the literature. Another conceivable
avantage of the presence of the N-Boc group might be the opening of the lactam by nucleophiles21
(alcoholate, amine, Grignard reagent, organolithium compound, aminoester) to provide aminoamides,
aminoesters, aminoketones, etc.
Scheme 5.
In conclusion, we have shown a new synthetic application of a γ-lactam derived from (R)-
phenylglycinol. Using the chiral α,β-unsaturated lactam 1, new asymmetric routes towards 5, 4,5- and
3,5-substituted pyrrolidones are under investigation and will soon be published.
3. Experimental
All the starting materials were commercially available and purified following standard techniques.
(R)-(−)-Phenylglycinol was prepared according to the literature procedure.22 THF was freshly distilled
from sodium–benzophenone ketyl and methanol from magnesium iodine. sec-BuLi (1.6 M in hexane)
was purchased from Aldrich. Product purification was performed by flash chromatography on silica gel
(Merck art. 9305).
Optical rotations were measured at room temperature on a Perkin–Elmer 241 polarimeter. IR spectra
1
were recorded on a Nicolet 205 FT-IR spectrophotometer. The H NMR and 13C NMR spectra were
recorded on a Bruker AC-300, AC-250 or AC-200 instrument using Me4Si as internal standard. Mass
spectra were recorded on an AEI MS-9 (CI; isobutane) or AEI MS-50 (EI) instrument. Elemental analyses
were performed by the Microanalysis Laboratory at the Institut de Chimie des Substances Naturelles
(Gif-sur-Yvette).
3.1. 1-(2-Hydroxy-1-phenylethyl)-1,5-dihydropyrrol-2-one 1
To a solution of 2,5-dimethoxy-2,5-dihydrofuran (4.44 ml, 36.5 mmol) and (R)-(−)-phenylglycinol
(5.0 g, 36.5 mmol) in water (150 ml) was added a conc. solution of HCl (4.5 ml). The mixture was
stirred at room temperature for 3 h then neutralized with solid NaHCO3 and extracted with CH2Cl2.
The combined organic layers were dried over MgSO4 and the solvent distilled off. The residual red oil
was purified by flash chromatography (CH2Cl2:MeOH=96:4) to give the α,β-unsaturated-γ-lactam 1 as
a red solid. Yield: 75% (5.13 g); mp: 103°C (heptane–AcOEt); [α]D −21 (c=1.0, CH2Cl2); IR (film): ν
1
(cm−1) 3400 (OH st), 1653 (C_O st), 797, 725 (HC_CH cis); H NMR (250 MHz, CDCl3): δ (ppm)
7.25–7.30 (5H, m), 7.00 (1H, d, 5.9 Hz), 6.10 (1H, d, 5.9 Hz), 5.25 (1H, dd, 5.1, 7.7 Hz), 4.65 (1H, sl),

I. Baussanne et al. / Tetrahedron: Asymmetry 9 (1998) 797–804
801
4.00–4.15 (3H, d+m, 20.5 Hz), 3.80 (1H, d, 20.5 Hz); 13C NMR (62.5 MHz, CDCl3): δ (ppm) 172.2,
143.8, 137.7, 128.5, 127.5, 127.2, 127.1, 62.5, 57.7, 50.9; MS (EI): m/z 203 (M+), 185 (M+−H2O), 172
(M+−CH2OH), 144 (172−CO), 104 (Ph-CH_CH2), 91 (PhCH2); anal. calcd for C12H13NO2: C, 70.92;
H, 6.45; N, 6.89; found: C, 70.52; H, 6.39; N, 6.92.
3.2. 1-(2-Hydroxy-1-phenylethyl)-pyrrolidin-2-one 8
A solution of 1 (4.42 g, 0.021 mmol) in dry methanol (25 mL) and 10% Pd–C (0.1 g) were stirred
at room temperature for 1 h under a hydrogen atmosphere (1 atm). The mixture was filtered and
concentrated in vacuo. After purification by flash chromatography (CH2Cl2:MeOH=96:4), pyrrolidin-
2-one 8 was isolated as a colourless oil. Yield: 85% (3.79 g); [α]D −54 (c=3.4, CH2Cl2); IR (film): ν
1
(cm−1) 3400 (OH st), 1662 (C_O st); H NMR (300 MHz, CDCl3): δ (ppm) 7.30 (5H, m), 5.18 (1H,
dd, 6.0, 7.7 Hz), 4.40 (1H, bs), 4.05 (2H, m), 3.45 (1H, dd, 8.5, 14 Hz), 3.16 (1H, m), 2.44 (2H, m), 1.98
(2H, m); 13C NMR (62.5 MHz, CDCl3): δ (ppm) 176.3, 136.8, 128.5, 127.6, 127.3, 61.4, 57.7, 44.4,
31.4, 17.8; MS (CI): m/z 206 (MH+); anal. calcd for C12H15NO2: C, 70.22; H, 7.38; N, 6.82; found: C,
70.42; H, 7.35; N, 6.78.
3.3. General procedure for the alkylation of 8
To a solution of lactam 8 (1 equiv.) in THF, sec-BuLi (1.6 M in hexane, 2.5 equiv.) was slowly
added at −78°C under a nitrogen atmosphere. The mixture was stirred for 20 min and alkyl halide (2
equiv.) was added dropwise. After stirring at −78°C or 0°C (depending on the electrophile), the mixture
was hydrolyzed by addition of saturated NH4Cl solution and extracted several times with CH2Cl2. The
combined organic layers were dried over MgSO4 and the solvent was evaporated. The crude product was
purified by flash chromatography.
3.4. 1-(2-Hydroxy-1-phenylethyl)-3-methyl-pyrrolidin-2-one 9a
From lactam 8 (699 mg; 3.41 mmol) and methyl iodide; stirred for 1 h at −78°C; chromatography using
CH2Cl2:MeOH (95:5); yield: 87% (652 mg); d.e.: 80%; amorphous solid; [α]D −34 (c=1.0, CH2Cl2);
IR (film): ν (cm−1) 3400 (OH st), 1669 (C_O st); 1H NMR (250 MHz, CDCl3): δ (ppm) 7.20–7.40 (5H,
m), 4.92 (1H, dd, 4.5, 8.6 Hz), 4.15 (1H, m), 4.05 (1H, m), 3.50 (1H, m), 3.29 (1H, ddd, 7.4, 8.8, 9.6
Hz), 3.1 (1H, ddd, 2.9, 8.8, 9.6 Hz), 2.61 (1H, m), 2.24 (1H, m), 1.63 (1H, m), 1.25 (3H, d, 7.0 Hz); 13
C
NMR (62.5 MHz, CDCl3): δ (ppm) 178.4, 137.1, 128.4, 127.4, 127.1, 61.4, 57.5, 42.2, 37.0, 27.1, 15.9;
MS (CI): m/z 220 (MH+); anal. calcd for C13H17NO2: C, 71.21; H, 7.81; N, 6.39; found: C, 71.01; H,
8.05; N, 6.28.
3.5. 1-(2-Hydroxy-1-phenylethyl)-3-propylpyrrolidin-2-one 9b
From lactam 8 (329 mg, 1.60 mmol) and propyl bromide; stirred for 1 h at −78°C and 2 h at 0°C;
chromatography using CH2Cl2:MeOH (98:2); yield: 52% (207 mg); d.e.: 90%; pale yellow oil; [α]D
−20 (c=1.4, CH2Cl2); 1H NMR (300 MHz, CDCl3): δ (ppm) 7.30 (5H, m), 5.18 (1H, t, 6.8 Hz), 4.3 (1H,
bs), 4.10 (2H, d, 6.3 Hz), 3.35 (1H, ddd, 8.1, 9.1, 9.0 Hz), 3.1 (1H, ddd, 3.0, 9.1, 9.1 Hz), 2.50 (1H, m),
2.15 (1H, m), 1.85 (1H, m), 1.60 (1H, m), 1.30 (3H, m), 1.0 (3H, t, 7 Hz); 13C NMR (75.3 MHz, CDCl3):
δ (ppm) 178.3, 137.1, 128.6, 127.7, 127.3, 61.93, 58.23, 43.0, 42.3, 33.2, 25.0, 20.2, 13.9; MS (CI): m/z
248 (MH+); anal. calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66; found: C, 72.77; H, 8.77; N, 5.36.

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3.6. 1-(2-Hydroxy-1-phenylethyl)-3-butylpyrrolidin-2-one 9c
From lactam 8 (566 mg, 2.76 mmol) and butyl iodide; stirred for 1.5 h at −78°C and 1.5 h at 0°C;
chromatography using CH2Cl2:MeOH (96.5:3.5); yield: 60%; d.e.: 81% (432 mg); yellow oil; [α]D
1
−11.5 (c=1.0, CH2Cl2); IR (film): ν (cm−1) 3400 (OH st), 1662.5 (C_O st); H NMR (300 MHz,
CDCl3): δ (ppm) 7.20–7.40 (5H, m), 5.15 (1H, t, 6.4 Hz), 4.2 (1H, bs), 4.10 (2H, d, 6.2 Hz), 3.38
(1H, ddd, 3.5, 9.0, 9.5 Hz), 3.1 (1H, dd, 7.8, 9.6 Hz), 2.50 (1H, m), 2.19 (1H, m), 1.85 (1H, m), 1.60 (1H,
m), 1.35 (5H, m), 0.9 (3H, m); 13C NMR (62.5 MHz, CDCl3): δ (ppm) 177.9, 137.1, 128.4, 127.4, 127.1,
61.4, 57.4, 42.4, 42.1, 30.6, 29.0, 24.8, 22.4, 13.7; MS (CI): m/z 262 (MH+); anal. calcd for C16H23NO2:
C, 73.53; H, 8.87; N, 5.36; found: C, 73.59; H, 8.68; N, 5.58.
3.7. 1-(2-Hydroxy-1-phenylethyl)-3-benzylpyrrolidin-2-one 9d
From lactam 8 (210 mg, 1.02 mmol) and benzyl bromide; stirred for 1 h at −78°C; chromatography
using AcOEt:heptane (7:3); yield: 83%; d.e.: 87% (256 mg); colourless oil; [α]D +33 (c=1.5, CH2Cl2);
1
IR (film): ν (cm−1) 3400 (OH st), 1662.5 (C=O st); H NMR (300 MHz, CDCl3): δ (ppm) 7.25 (10H,
m), 5.14 (1H, t, 6.7 Hz), 4.17 (1H, bs), 4.07 (2H, d, 7.0 Hz), 3.28 (1H, dd, 7.9, 9.2 Hz), 3.19 (1H, dd,
3.9, 13.5 Hz), 2.95 (1H, dt, 3.1, 9.2 Hz), 2.84 (1H, ddt, 3.9, 8.9, 9.2 Hz), 2.7 (1H, dd, 9.2, 13.5 Hz),
2.10 (1H, m), 1.66 (1H, m); 13C NMR (62.5 MHz, CDCl3): δ (ppm) 177.3, 139.2, 136.9, 129.1, 129.8,
128.4, 127.8, 127.4, 126.3, 62.1, 58.6, 44.2, 43.1, 36.8, 24.3; MS (CI): m/z 296 (MH+); anal. calcd for
C19H21NO2: C, 77.26; H, 7.16; N, 4.74; found: C, 77.41; H, 7.38; N, 4.61.
3.8. (3S)-3-Methylpyrrolidin-2-one 10
In a two-necked flask fitted with a dry-ice condenser, were placed lactam 9a (234 mg, 1.07 mmol,
d.e.=80%) anhydrous THF (10 ml) and anhydrous EtOH (0.6 mL, 10.7 mmol). The mixture was chilled
to −78°C under a nitrogen atmosphere. Ammonia (40 ml) was condensed, then small pieces of lithium
were added until the dark blue coloration persisted for more than 5 min. The mixture was stirred at −78°C
for 30 min, then the cooling bath was removed to allow evaporation of NH3. The solution was quenched
with a saturated aqueous solution of NH4Cl and extracted with CH2Cl2. The combined organic layers
were dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography
(CH2Cl2:MeOH=96:4) to give lactam 10 as a yellow oil, yield: 77% (81 mg); this compound exhibited
analytical data identical to those reported in the literature.13
3.9. (4S)-4-Methyl-5-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester 12
To a solution of pyrrolidinone 10 (103 mg, 1.04 mmol) in anhydrous THF (2 ml) were added DMAP
(116 mg, 1.04 mmol) and (Boc)2O (375 mg, 2.6 mmol). The mixture was stirred at room temperature for
4 h. The solvent was distilled off and the residue dissolved in CH2Cl2. The solution was filtered through
a small amount of silica gel 60. After the evaporation of the solvent, the product 12 was obtained with
satisfactory purity. Yield: 85% (176 mg); yellow oil; IR (film): ν (cm−1) 1785, 1754 (C_O Boc st), 1712
1
(C_O amide st): H NMR (300 MHz, CDCl3): δ (ppm)=3.78 (1H, ddd, 2.5, 8.7, 10.8 Hz), 3.61 (1H,
m), 2.57 (1H, m), 2.25 (1H, m), 1.67 (1H, m), 1.60 (9H, s), 1.22 (3H, d, 7.1 Hz); 13C NMR (62.5 MHz,
CDCl3): δ (ppm)=176.2, 145.0, 82.1, 44.0, 39.1, 27.6, 26.0, 15.0.

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803
3.10. (2S)-4-tert-Butoxycarbonylamino-2-methyl-butyric acid 13
To a solution of lactam 12 (68 mg, 0.34 mmol) in THF:H2O (2:1, 1 ml) was added LiOH·H2O (42
mg, 1 mmol). The mixture was stirred at room temperature for 1 h then acidified to pH 1–2 with 0.5
N HCl solution. After extraction with Et2O, the combined organic layers were dried over MgSO4 then
concentrated in vacuo. The residue was purified by flash chromatography (CH2Cl2:MeOH=96:4). The
N-Boc-amino acid 13 was obtained in 76% yield (56 mg); e.e.: 80%; colourless oil; [α]D +11 (c=1.0,
CH2Cl2); [lit.23 for the (2R)-enantiomer with 100% e.e: [α]D −14 (c=0.31, CH2Cl2)]; anal. calcd for
C10H19NO4: C, 55.28; H, 8.81; N, 6.45; found: C, 55.87; H, 8.42; N, 5.66. All spectroscopic data are
identical to those reported in the literature23 for the 2R enantiomer.
Acknowledgements
We wish to thank Prof. H.-P. Husson for fruitful discussions and for his interest in this work. We
acknowledge the Ministère de l’Enseignement Supérieur et de la Recherche for a fellowship for I. B.,
and Mrs. M.-A. Billion for GC–MS measurements.
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