Chemoenzymatic enantioselective synthesis of 3-hydroxy-2-pyrrolidinones and 3-hydroxy-2-piperidinones

Article abstract of DOI:10.1016/S0957-4166(03)00548-2

The enantioselective synthesis of 3-hydroxypyrrolidin-2-ones and 3-hydroxy piperidin-2-ones has been carried out in high enantiomeric excess employing immobilized lipase from Pseudomonas cepacia.

Full text of DOI:10.1016/S0957-4166(03)00548-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2587–2594
Chemoenzymatic enantioselective synthesis of
3-hydroxy-2-pyrrolidinones and 3-hydroxy-2-piperidinones
Ahmed Kamal,* K. Venkata Ramana, A. Venkata Ramana and A. Hari Babu
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology,
Hyderabad 500007, India
Received 19 May 2003; accepted 14 July 2003
Abstract—The enantioselective synthesis of 3-hydroxypyrrolidin-2-ones and 3-hydroxy piperidin-2-ones has been carried out in
high enantiomeric excess employing immobilized lipase from Pseudomonas cepacia.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
methods are laborious and have limitations from the
practical point of view, especially due to the use of
expensive cofactors and very long reaction times. Some
of the enzymatic methodologies mentioned in the litera-
ture employ alcohol dehydrogenase, hence these are
expensive and lack practical applicability.
Hydroxy substituted nitrogen heterocycles containing
five- and six-membered rings are well known in nature
and are components of many compounds with valuable
pharmacological properties.1 For instance, these N-sub-
stituted pyrrolidinones are of interest for the treatment
of brain insufficiencies and as cognition activators.2 In
view of their low toxicities these have recently attracted
much attention in the pharmaceutical arena.3 In addi-
tion, several syntheses have been reported employing
the racemic core of particularly, 3-hydroxy-2-pyrrolidi-
nones as valuable building blocks for medicinally
important compounds. However, the configuration at
the 3-position in this heterocycle has exhibited extraor-
dinary influence on the biological properties for some
compounds by employing this as a precursor. Several
examples in this context have been investigated which
led to the development of enantioselective synthetic
strategies for these 3-hydroxy substituted lactams.
2. Results and discussion
There has been considerable interest in our laboratory
for the total synthesis of natural products particularly
employing chiral intermediates obtained through bio-
transformations or enzyme mediated processes.11 In
continuation of these efforts, a chemoenzymatic strat-
egy has been investigated towards the synthesis of
non-racemic chiral 3-hydroxylactams. In this chemoen-
zymatic process, the lactams have been synthesized
starting from very economical starting materials, g-
butyrolactone or d-valerolactone as shown in Scheme 1.
The synthesis involves use of red phosphorus and
bromine at 90°C to obtain the corresponding tribromo
compounds 5–6, which on treatment with appropriate
amine followed by NaH afforded the N-substituted
3-bromolactams 9–10. The racemic 3-acetoxylactams
11–12 have been obtained in quantitative yields from
their 3-bromolactams in presence of KOAc/18-crown-6.
In recent years, both chemical and enzymatic routes
have been developed towards the enantioselective syn-
thesis of 3-hydroxy substituted lactams particularly,
3-hydroxy-2-pyrrolidinone and 3-hydroxy-2-piperidi-
none.3a,4–6 In the literature two conventional methods
have been reported for the chiral 3-hydroxy-2-pyrrolidi-
nones that involve laborious crystallization methodol-
ogy and derivatization processes.7,8 Recently, enzymatic
processes have also been reported involving lactate
dehydrogenase-catalyzed reductions.9,10 Most of these
The subsequent resolution of the acetoxy precursors
has been achieved by adopting a lipase-catalyzed alco-
holysis. This strategy was chosen as it provides an easy
product recovery and also it minimizes side reactions
that may be expected in this class of substrates. The
* Corresponding author. E-mail: ahmedkamal@iict.ap.nic.in
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00548-2

2588
A. Kamal et al. / Tetrahedron: Asymmetry 14 (2003) 2587–2594
Scheme 1.
conversion of acetate 11a to (S)-1a has been achieved
by employing the immobilized lipases from Pseu-
domonas cepacia viz., ‘Amano’ PS-C lipase (ꢀ1100
U/mg), immobilized on chemically modified ceramic
and ‘Amano’ PS-D lipase (ꢀ899 U/mg), immobilized
on diatomaceous earth in 18 and 24 h, respectively, as
shown in Scheme 2. Interestingly, lipase from the same
source without immobilization has not given satisfac-
tory results. Thus, this observation shows the impor-
tance of employing immobilized lipases. ‘Amano’ PS-C
lipase has been found to be suitable for the resolution
of such substrates. The corresponding alcohol (R)-1a
and acetate (S)-11a have been obtained in >99% e.e.
with 50% conversion while ‘Amano’ PS-D lipase
afforded compound (R)-1 in 50% e.e. with 40%
conversion.
Scheme 2.
This resolution process has been extended for the 3-acet-
oxy-2-piperidinones 12 as shown in Scheme 3. In this
investigation the effect of N-substitution on these sub-
strates for the lipase-mediated resolution has also been
examined 11b–d/12a–d. The corresponding 3-hydroxy-
2-pyrrolidinones, 3-hydroxy-2-piperidinones and their
acetates are obtained in 55 to >99% e.e. employing
Amano PS-C lipase as illustrated in Table 1.
Scheme 3.
The effects of solvents have also been studied for this
lipase-mediated resolution process and it was observed
that this process is faster in polar solvents such as
acetonitrile compared to the nonpolar solvents such as
toluene. However, THF has been found to provide
Table 1. Amano PS-C lipase-mediated alcoholysis of 3-acetoxy-2-pyrrolidinones and 3-acetoxy-2-piperidinones
Substrate
°C
h
%e.e.a OH
% e.e.a OAc
% Conversion
Eb
11a
11b
11c
11d
12a
12b
12c
12d
28
28
28
28
45
45
45
28
20
24
24
18
24
28
28
18
>99
98
97
nd
>99
nd
>99
95
>99
45
90
98
50
47
49
45
44
45
49
50
1057
282
227
nd
473
nd
nd
>99
96
>99
nd
1057
°C=temperature, h=time, nd=not determined.
a Chiral HPLC analysis.
b Enantiomeric ratio.13

A. Kamal et al. / Tetrahedron: Asymmetry 14 (2003) 2587–2594
2589
Figure 1.
good conversions with high enantiomeric excess. The
differences in the temperature, reaction rates and effects
of solvents in the resolution of acetates 11a–d and
12a–d may be attributed to a cumulative effect of
interactions between lipase, substrate, carrier and sol-
vent working in tandem.
70°C and an additional quantity of bromine (40.43 g,
0.25 mol) was added over a 30 min interval. After the
completion of the addition of bromine, the temperature
was raised to 80°C and maintained at that temperature
for 3 h. Air was blown into the reaction mixture to
remove excess of bromine and HBr completely. This
reaction mixture was then distilled to obtain 45 g (63%)
of the 2,4-dibromobutyric acid bromide 5 as a colorless
liquid.
In conclusion, an efficient and practical chemoenzy-
matic enantioselective synthesis of 1 and 2 has been
achieved employing ‘Amano’ PS-C lipase-mediated
alcoholysis. The present methodology has several
advantages over the existing procedures and may find
use towards the synthesis of biologically important
compounds employing 1 and 2 as precursors in their
homochiral form (Fig. 1).
3.2. General procedure for the preparation of butyric
acid amides 7a–c and 8a–c
To a mixture containing 10 ml of 28% aqueous amine,
15 ml water, 50 ml of CHCl3, a solution 2,4-dibro-
mobutyric acid bromide 5 (10g, 0.32 mmol) was added
dropwise at 10–15°C. After the completion of the addi-
tion, the temperature was raised to 30°C and stirred for
30 min. The phases in reaction mixture were then
separated and the aqueous layer was extracted with
chloroform. The combined organic layers were washed
with brine, dried over MgSO4 to obtain crude solid.
The solid thus obtained was washed with diethyl ether-
hexane 1:1 solvent mixture to obtain dibromoamides 7
and 8 as white solids.
3. Experimental
Unless specified all solvents were reagent grade and
used without purification. Melting points have been
recorded on an electrothermal apparatus and are
1
uncorrected. H NMR spectra were recorded as solu-
tions in CDCl3 and the chemical shifts are reported as
parts per million (ppm, l) on a 200 MHz instrument.
Coupling constants are reported in hertz (Hz). Spectral
patterns are designated as s, singlet; d, doublet; t,
triplet; br, broad; m, multiplet. EI mass spectra were
recorded on a VG 7070H micromass mass spectrometer
at 200°C, 7 eV with a trap current of 200 mA and 4 kV
acceleration voltage. Analytical TLC of all reactions
was performed on Merck precoated plates (silica gel
60F-254 on glass). Column chromatography was per-
formed using Acme silica gel (60–120 mesh). HPLC
analysis was performed on an instrument that consisted
of a Shimadzu LC-6A system controller, SPD-6A fixed
wave length UV monitor as detector, FCV-100B frac-
tion collector and chromatopac C-R4A data processor
as a recording integrator.
3.3. 2,4-Dibromo butyric acid amide 7a
This compound was obtained following the above pro-
cedure using compound 5 (10g, 32 mmol) and 15 ml
1
aqueous ammonia. Yield: 5.1 g, 65%; mp: 79–81°C; H
NMR (200 MHz, CDCl3): l 2.40–2.50 (m, 1H), 2.60–
2.70 (m, 1H), 3.50–3.65 (m, 2H), 4.50–4.60 (m, 1H),
6.10–6.40 (br s, 2H).
3.4. N-Methyl-2,4-dibromo butyric acid amide 7b
This compound was obtained following the above pro-
cedure using compound 5 (10g, 32 mmol) and 10 mL of
40% aqueous methyl amine. Yield: 6.0 g, 72%; mp:
1
53–56°C; H NMR (200 MHz, CDCl3): l 2.40–2.60 (m,
3.1. Preparation of 2,4-dibromobutyric acid bromide 5
1H), 2.65–2.80 (m, 1H), 2.9 (d, 3H J=3.0 Hz), 3.50–
3.60 (m, 2H), 4.50–4.60 (m, 1H), 6.35–6.45 (br s, 1H).
In a three-necked round bottom flask equipped with a
dropping funnel and an efficient condenser were placed
freshly distilled g-butyrolactone 3 (20 g, 0.23 mol) and
red phosphorous (2.5 g, 0.43 g atom). To this bromine
(40.43 g, 0.25 mol) was added over a half an hour
interval, while the mixture was being stirred moderately
and cooled in an ice bath. The mixture was heated to
3.5. N-Ethyl-2,4-dibromo butyric acid amide 7c
This compound was prepared according to the above
procedure from 2,4-dibromo butyric acid bromide 5
(10g, 32 mmol) and 10 mL of aqueous ethylamine.
1
Yield: 6.2 g, 70%; mp: 59–61°C; H NMR (200 MHz,

2590
A. Kamal et al. / Tetrahedron: Asymmetry 14 (2003) 2587–2594
CDCl3): l 1.20–1.30 (t, 3H, J=5.0 Hz), 2.40–2.50 (m,
1H), 2.7–2.8 (m, 1H), 3.50–3.70 (m, 4H), 4.60–4.70 (m,
1H), 6.20–6.35 (br s, 1H).
of 2,5-dibromopentanoic acid bromide 6 (5 g, 15 mmol)
at zero degrees. The reaction was then brought to rt
and stirred for 1 h. The reaction mixture was washed
with water and the CH2Cl2 layer dried over Na2SO4,
before concentration to obtain a residue which was
purified by silica gel column chromatography using
hexane: acetone gradient to obtain the product. Yield:
7.9 g, 85%; mp: 65–68°C; H NMR (200 MHz, CDCl3):
l 2.00–2.40 (m, 4H), 3.55–3.70 (m, 2H), 4.45–4.80 (m,
3H), 7.20–7.40 (m, 5H).
3.6. N-Benzyl-2,4-dibromo butyric acid amide 7d
To a solution of benzyl amine (1.8 g, 16 mmol) in dry
CH2Cl2 was added triethyl amine and a solution of
2,4-dibromo butanoic acid bromide 5 (5 g, 16 mmol) in
CH2Cl2 at zero degrees. The reaction was then brought
to rt and stirred for 1 h. The reaction mixture was
washed with water and the CH2Cl2 layer dried over
Na2SO4 and concentrated to obtain a residue. The
crude residue thus obtained was purified by silica gel
(60–120 mesh) column chromatography using hexane:
acetone gradient to obtain the product amide 7d. Yield:
8.10 g in 83%; mp: 61–64°C; 1H NMR (200 MHz,
CDCl3): l 2.30–2.50 (m, 1H), 2.60–2.80 (m, 1H), 3.40–
3.60 (m, 2H), 4.30–4.60 (m, 3H), 6.60–6.70 (br s, 1H),
7.20–7.40 (m, 5H).
1
3.12. 3-Bromo-2-pyrrolidinone 9a
To a solution of 2,4-dibromobutyramide 7a (5 g, 20
mmol) in THF was added NaH (0.980 g, 40 mmol)
slowly at 0–10°C and stirred at rt for 1 h. The reaction
was monitored by TLC. The reaction mixture was
concentrated and the residue obtained was taken into
ice-cold water and extracted with CHCl3. The chloro-
form layer was then washed with brine dried over
Na2SO4 and concentrated to obtain crude compound.
Purification of the crude compound with hexane: ace-
tone mixture gave the title compound. Yield: 1.3 g, 30%
3.7. 2,5-Dibromovaleric acid bromide 6
1
This compound was prepared according to the proce-
dure described for the preparation of 2,4-dibromobu-
tyric acid bromide 5 with the starting materials
l-valerolactone 4 (20g, 0.2 mol), red phosphorous (0.2
g atom) and two portions of bromine (34 g, 0.21 mol)
each. Compound 6 (40 g) was obtained as a liquid after
distilling once.
yield; mp: 79–81°C; H NMR (200 MHz, CDCl3): l
2.30–2.40 (m, 1H), 2.65–2.80 (m, 1H), 3.40–3.50 (m,
1H), 3.50–3.60 (m, 1H), 4.20–4.30 (m, 1H), 7.60 (br s,
1H); EIMS: m/z 163 [M+], 165 [M++2].
3.13. 3-Bromo-1-methyl-2-pyrrolidinone 9b
This compound was prepared from 2,4-dibromo-N-
methylbutyramide 7b (5.5g, 21 mmol) and sodium
hydride (0.960 g, 40 mmol). The product was obtained
as a liquid. Yield: 2.8 g, 80% yield; 1H NMR (200
MHz, CDCl3): l 2.00–2.20 (m, 1H), 2.40–2.55 (m, 1H),
3.00 (s, 3H), 3.30–3.40 (m, 1H), 3.55–3.65 (m, 1H),
4.40–4.45 (m, 1H); EIMS: m/z 177 [M+], 179 [M++2].
3.8. 2,5-Dibromovaleric acid amide 8a
This compound was obtained following the above pro-
cedure using compound 6 (10 g, 30 mmol) and 15 ml of
28% aqueous ammonia. Yield: 5.3 g, 66%; mp: 85–
1
88°C; H NMR (200 MHz, CDCl3): l 2.00–2.40 (m,
4H), 3.35–3.45 (t, 2H, J=5.4 Hz), 4.30–4.40 (m, 1H),
6.05–6.25 (br s, 1H), 6.25–6.65 (br s, 1H).
3.14. 3-Bromo-1-ethyl-2-pyrrolidinone 9c
3.9. N-Methyl-2,5-dibromovaleric acid amide 8b
This compound was prepared from 2,4-dibromo-N-
ethylbutyramide 7c (5 g, 19 mmol) and sodium hydride
(0.920 g, 40 mmol). The product was obtained as a
This compound was obtained following the above pro-
1
cedure using compound 6 (10g, 30 mmol) and 10 ml of
liquid. Yield: 2.7 g, 75%; H NMR (200 MHz, CDCl3):
1
40% aqueous methylamine. Yield: 5.7 g, 68%; H NMR
l 1.20–1.30 (t, 3H, J=7 Hz), 2.25–2.45 (m, 1H), 2.60–
2.80 (m, 1H), 3.30–3.45 (q, 2H, J=6.5 Hz), 3.60–3.80
(m, 2H), 4.40–4.50 (1H, t); EIMS: m/z 191 [M+].
(200 MHz, CDCl3): l 2.00–2.40 (m, 4H), 2.80–2.90 (d,
3H, J=3.5 Hz), 3.40–3.50 (t, 2H, J=5.4 Hz), 4.30–4.40
(m, 1H), 6.40–6.70 (br s, 1H).
3.15. 3-Bromo-1-benzyl-2-pyrrolidinone 9d
3.10. N-Ethyl-2,5-dibromovaleric acid amide 8c
This compound was prepared from 2,4-dibromo-N-
benzylbutyramide 7d (5 g, 14 mmol) and sodium
hydride (0.740 g, 30 mmol). The product was obtained
This compound was prepared according to the above
procedure from 2,5-dibromovaleric acid bromide 6 (10
g, 30 mmol) and 10 mL of aqueous ethyl amine. Yield:
1
as a liquid. Yield: 3.2 g, 88%; H NMR (200 MHz,
1
6.3 g, 72%; mp: 63–65°C; H NMR (200 MHz, CDCl3):
CDCl3): l 2.35–2.55 (m, 1H), 2.55–2.75 (m, 1H), 3.60–
3.80 (m, 2H), 4.30–4.55 (m, 2H), 4.40 (t, 1H), 7.20–7.60
(m, 5H). EIMS: m/z 253 [M+].
l 1.15–1.25 (t, 3H, J=5.0 Hz), 2.00–2.40 (m, 4H),
3.25–3.40 (q, 2H, J=5.0 Hz, 4.8 Hz), 3.40–3.50 (t, 2H,
J=5.0 Hz), 4.30–4.40 (m, 1H), 6.45–6.65 (br s, 1H).
3.16. 3-Bromo-2-piperidinone 10a
3.11. N-Benzyl-2,5-dibromovaleramide 8d
This compound was prepared according to the proce-
dure described for the conversion of compounds 7a–c
to lactams 9a–c from 2,5-dibromovaleramide 8a (5.5 g,
To a solution of benzyl amine (1.7 g, 15.8 mmol) in dry
CH2Cl2 was added 9.0 g of triethylamine and a solution

A. Kamal et al. / Tetrahedron: Asymmetry 14 (2003) 2587–2594
2591
21 mmol) and sodium hydride (1.0 g, 42 mmol). Yield:
3.22. 3-Acetoxy-1-ethyl-2-pyrrolidinone 11c
1.5 g, 40%; mp: 114–117°C; 1H NMR (200 MHz,
CDCl3): l 1.80–1.90 (m, 1H), 2.20–2.40 (m, 3H), 3.20–
3.50 (m, 2H), 4.50–4.60 (t, 1H, J=6.8 Hz), 6.00 (br s,
1H); EIMS: m/z 177 [M+], 179 [M++2].
This compound was prepared from 3-bromo-1-ethyl-2-
pyrrolidinone 9c (2.5 g, 13 mmol), potassium acetate
(5.5 g. 56 mmol) and 18-crown-6 (0.050 g, 0.20 mmol).
The product was obtained as a liquid. Yield: 2.30 g,
1
97%; H NMR (200 MHz, CDCl3) l 1.20–1.30 (t, 3H,
3.17. 3-Bromo-1-methyl-2-piperidinone 10b
J=7.7 Hz), 1.85–1.95 (m, 1H), 2.15 (s, 3H), 2.45–2.60
(m, 1H), 3.40–3.60 (m, 4H), 5.2 (t, 1H, J=6.0 Hz);
EIMS: m/z 111 [M+ –60].
This compound was prepared from N-methyl-2,5-
dibromovaleramide 8b (5 g, 18 mmol) and sodium
hydride (0.770 g, 32 mmol). The product was obtained
3.23. 3-Acetoxy-1-benzyl-2-pyrrolidinone 11d
1
as a liquid. Yield: 2.4 g, 70%; H NMR (200 MHz,
CDCl3): l 1.80–1.90 (m, 1H), 2.20–2.40 (m, 3H), 3.00
(s, 3H), 3.20–3.50 (m, 2H), 4.50–4.60 (t, 1H, J=6.8
Hz); EIMS: m/z 191 [M+], 193 [M++2].
This compound was prepared from 3-bromo-1-benzyl-
2-pyrrolidinone 9d (2.5 g, 10 mmol), potassium acetate
(3.9 g, 39.6 mmol) and 18-crown-6 (0.05 g, 0.20 mmol).
The product was obtained as a liquid. Yield: 2.2 ml,
96%; 1H NMR (200 MHz, CDCl3): l 1.80–2.00 (m,
1H), 2.10 (s, 3H), 2.50–2.65 (m, 1H), 3.20–3.35 (m, 2H),
4.3 (d, 2H, J=8.5 Hz), 5.2 (t, 1H, J=6.6 Hz), 7.15–7.40
(m, 5H); EIMS: m/z 173 [M+−60].
3.18. 3-Bromo-1-ethyl-2-piperidinone 10c
This compound was prepared from of 2,5-dibromo-N-
ethylvaleramide 8c (5 g, 17.5 mmol) and sodium
hydride (0.84 g, 35 mmol). The product was obtained as
a liquid. Yield: 2.5 g, 72%; 1H NMR (200 MHz,
CDCl3): l 1.10–1.20 (3H, t, J=7 Hz), 1.80–2.00 (m,
1H), 2.20–2.40 (m, 3H), 3.30–3.40 (m, 4H), 4.40–4.50
(m, 1H); EIMS: m/z 205 [M+], 207 [M++2].
3.24. 3-Acetoxy-2-piperidinone 12a
This compound was prepared from 3-bromo-2-piperidi-
none 10a (1.0 g, 5.6 mmol), potassium acetate (2.2 g,
22.5 mmol) and 18-crown-6 (0.05 g, 0.20 mmol). The
product was obtained as a solid. Yield: 830 mg, 94%;
mp: 69–71°C; 1H NMR (200 MHz, CDCl3): l 1.70–1.90
(m, 3H), 2.15–2.25 (m, 4H), 3.30–3.45 (m, 2H), 5.2 (t,
1H, J=5 Hz), 7.40 (br s, 1H); EIMS: m/z 157 [M+], 114
[M+−43].
3.19. 3-Bromo-1-benzyl-2-piperidinone 10d
This compound was prepared from 5 g of 2,5-dibromo-
N-benzylvaleramide 8d (5 g, 14 mmol) and sodium
hydride (0.69 g, 28 mmol). The product was obtained as
a liquid. Yield: 3.2 g, 87%; 1H NMR (200 MHz,
CDCl3): l 1.70–1.90 (m, 1H), 2.15–2.35 (m, 3H), 3.20–
3.40 (m, 2H), 4.30–4.40 (d, 1H, J=13 Hz), 4.55–4.60
(m, 1H), 4.65–4.80 (d, 1H J=13 Hz), 7.20–7.60 (5H,
m); EIMS: m/z 267 [M+], 269 [M++2].
3.25. 3-Acetoxy-1-methyl-2-piperidinone 12b
This compound was prepared from 3-bromo-1-methyl-
2-piperidinone 10b (2.5 g, 13 mmol), potassium acetate
(4.8 g, 49 mmol) and 18-crown-6 (0.05 g, 0.20 mmol).
The product was obtained as a liquid. Yield: 2.2 g,
98%; 1H NMR (200 MHz, CDCl3): l 1.60–1.80 (m,
3H), 2.00–2.20 (m, 4H), 2.90 (s, 3H), 3.20–3.50 (m, 2H),
5.20 (t, 1H, J=5 Hz); EIMS: m/z 171 [M+].
3.20. 3-Acetoxy-2-pyrrolidinone 11a
To a solution of 3-bromo-2-pyrrolidinone 9a (1.0 g, 6.1
mmol) in dry acetonitrile was added KOAc (2.4 g, 24
mmol) and 18-crown-6 (.050 g, 0.2 mmol). This was
refluxed for 5 h, while the reaction was monitored by
TLC. The reaction mixture was filtered after the com-
pletion of the reaction and concentrated to afford crude
solid product 11a. The crude product was purified by
column chromatography with hexane: acetone mixtures
on silica gel (60–120 mesh) to obtain the acetoxy com-
pound. Yield: 0.84 g, 96%; mp: 86–88°C; 1H NMR (200
MHz, CDCl3): l 1.90–2.10 (m, 4H), 2.30–2.70 (m, 1H),
3.30–3.50 (m, 2H), 5.20 (t, 1H, J=7.7 Hz), 7.90–8.00
(br s, 1H); EIMS: m/z 100 [M+−43].
3.26. 3-Acetoxy-1-ethyl-2-piperidinone 12c
This compound was prepared from 3-bromo-1-ethyl-2-
piperidinone 10c (2.5 g, 12 mmol), potassium acetate
(4.8 g, 49 mmol) and 18-crown-6 (0.05 g, 0.20 mmol).
The product was obtained as a liquid. Yield: 2.2 g,
1
98%; H NMR (200 MHz, CDCl3): l 1.10–1.20 (t, 3H,
J=6.4 Hz), 1.80–2.10 (m, 3H), 2.10–2.25 (m, 4H),
3.30–3.50 (m, 4H), 5.2 (1H, t, J=5.6 Hz); EIMS: m/z
185 [M+].
3.27. 3-Acetoxy-1-benzyl-2-piperidinone 12d
3.21. 3-Acetoxy-1-methyl-2-pyrrolidinone 11b
This compound was prepared from 3-bromo-1-benzyl-
2-piperidinone 10d (2.3 g, 9.3 mmol), potassium acetate
(3.6 g, 37 mmol) and 18-crown-6 (0.05 g, 0.20 mmol).
The product was obtained as a liquid. Yield: 2.2 g,
95%; 1H NMR (200 MHz, CDCl3): l 1.90–2.10 (m,
3H), 2.10–2.30 (m, 4H), 3.20–3.30 (m, 2H), 4.5 (s, 2H),
5.2 (m, 1H), 7.2 (m, 5H); EIMS: m/z 187 [M+−60] (loss
of OAc group).
This compound was prepared from 3-bromo-1-methyl-
2-pyrrolidinone 9b (2.5 g, 14 mmol), potassium acetate
(5.5 g, 56 mmol) and 18-crown-6 (0.05 g, 0.20 mmol).
The product was obtained as a liquid. Yield: 2.30 g,
95%; 1H NMR (200 MHz, CDCl3): l 1.90–2.10 (m,
4H), 2.30–2.70 (m, 1H), 3.0 (s, 3H), 3.30–3.50 (m, 2H),
5.20 (t, 1H, J=7.0 Hz); EIMS: m/z 157 [M+].

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A. Kamal et al. / Tetrahedron: Asymmetry 14 (2003) 2587–2594
3.28. 3-Hydroxy-2-pyrrolidinone 1a
3.33. 3-Hydroxy-1-methyl-2-piperidinone 2b
A solution of 3-acetoxy-2-pyrrolidinone 11a (0.400 g,
2.8 mmol) in methanol was stirred with K2CO3 (0.036
g, 0.30 mmol) at rt. The reaction was monitored by
TLC. After the completion of the reaction methanol
was evaporated and the crude solids were repeatedly
washed with acetone. The acetone extracts on concen-
tration gave crude solid, which on filtering over a
short silica gel pad with acetone yielded the 3-
hydroxy-2-pyrrolidinone as solid. Yield: 0.170 g, 60%;
1H NMR (200 MHz, CDCl3): l 1.95–2.20 (m, 1H),
2.40–2.60 (m, 1H), 3.20–3.35 (m, 2H), 4.25–4.40 (m,
2H), 7.0 (br s, 1H); EIMS: m/z 101 [M+].
This compound was obtained according to the proce-
dure described for the preparation of compound 1a
from 3-acetoxy-1-methyl-2-piperidinone 12b (0.500 g,
3.1 mmol) and K2CO3 (0.072 g, 0.60 mmol). The
product was obtained as a liquid. Yield: 0.250 g,
70%; 1H NMR (200 MHz, CDCl3): l 1.80–2.10 (m,
3H), 2.20–2.40 (m, 1H), 3.0 (s, 3H), 3.60–3.80 (br s,
1H), 3.95–4.10 (m, 1H).
3.34. 3-Hydroxy-1-ethyl-2-piperidinone 2c
This compound was obtained according to the proce-
dure described for the preparation of compound 1a
from 3-acetoxy-1-ethyl-2- piperidinone 12c (1.0 g, 5.8
mmol) and K2CO3 (0.150 g, 1.08 mmol). The product
was obtained as a liquid. Yield: 0.530 g, 93%; 1H
NMR (200 MHz, CDCl3): l 1.05–1.25 (t, 3H, J=5.8
Hz), 1.45–1.70 (m, 1H) 1.70–1.90 (m, 2H), 2.15–2.25
(m, 1H), 3.30–3.50 (m, 4H), 3.70–3.85 (br s, 1H),
3.90–4.00 (m, 1H).
3.29. 3-Hydroxy-1-methyl-2-pyrrolidinone 1b
This compound was obtained according to the proce-
dure described for the preparation of compound 1a
from 3-acetoxy-1-methyl-2-pyrrolidinone 11b (0.500 g,
3 mmol) and K2CO3 (0.072 g, 0.60 mmol). Yield:
1
0.207 g, 60%; H NMR (200 MHz, CDCl3): l 1.85–
2.00 (m, 1H), 2.10–2.20 (m, 1H), 2.90 (s, 3H), 3.20–
3.45 (m, 2H), 4.20–4.30 (t, 1H, J=6 Hz); EIMS: m/z
115 [M+].
3.35. 3-Hydroxy-1-benzyl-2-piperidinone 2d
This compound was obtained according to the proce-
dure described for the preparation of compound 1a
from 3-acetoxy-benzyl-2- piperidinone 12d (1.0 g, 4
mmol) and K2CO3 (0.110 g, 0.80 mmol). The product
was obtained as a liquid. Yield: 0.350 g, 85%; 1H
NMR (200 MHz, CDCl3): l 1.65–1.95 (m, 3H), 2.10–
2.30 (m, 1H), 3.10–3.25 (m, 2H), 3.60–3.90 (br s, 1H),
4.00–4.10 (dd, 1H, J=4.5 Hz, 7.1 Hz), 4.40–4.70 (dd,
2H, J=13 Hz, 16 Hz), 7.15–7.40 (m, 5H); EIMS: m/z
205 [M+].
3.30. 3-Hydroxy-1-ethyl-2-pyrrolidinone 1c
This compound was obtained according to the proce-
dure described for the preparation of compound 1a
from 3-acetoxy-1-ethyl-2-pyrrolidinone 11c (1.0 g, 6
mmol) and K2CO3 (0.140 g, 0.90 mmol). The product
was obtained as a liquid. Yield: 0.540 g, 90%; 1H
NMR (200 MHz, CDCl3): l 1.10–1.20 (t, 3H, J=5.5
Hz), 1.90–2.05 (m, 1H), 2.35–2.50 (m, 1H), 3.20–3.50
(m, 4H), 4.15–4.40 (m, 2H); EIMS: m/z 129 [M+], 111
[M+−18].
3.36. Enzymatic deacylation of 3-acetoxylactams
3.31. 3-Hydroxy-1-benzyl-2-pyrrolidinone 1d
To a solution of the acetoxy lactams 11a–d and 12a–
,
d (100 mg) in THF (50 mL) was added 4 A molecu-
This compound was obtained according to the proce-
dure described for the preparation of compound 1a
from 3-acetoxy-1-benzyl-2-pyrrolidinone 11d (1.0 g,
4.3 mmol) and K2CO3 (0.120 g, 0.85 mmol). The
product was obtained as a liquid. Yield: 0.700 g,
85%; 1H NMR (200 MHz, CDCl3): l 1.85–2.00 (m,
1H), 2.30–2.45 (m, 1H), 3.10–3.30 (m, 2H), 4.35–4.45
(m, 3H), 5.05–5.25 (br s, 1H), 7.15–7.40 (m, 5H);
EIMS: m/z 191 [M+].
lar sieves powder, lipase (110 mg) and 2-propanol (10
equiv.). This reaction mixture was stirred on a rotary
shaker. The reaction was monitored by TLC. After
the reaction proceeded for 50% conversion the molec-
ular sieves and the lipase were filtered off. The filtrate
was concentrated under reduced pressure and the
crude was purified by silica gel chromatography (60–
120 mesh, n-hexane:acetone). The structure analysis
data obtained for the alcohol and the acetate prod-
ucts matched well with the chemically obtained
racemic samples. HPLC analysis12 was done either for
the mixture of both acetate and alcohol or the pure
compounds for determination of chiral purities.
3.32. 3-Hydroxy-2-piperidinone 2a
This compound was obtained according to the proce-
dure described for the preparation of compound 1a
from 3-acetoxy-2-piperidinone 12a (0.400 g, 2.5
mmol) and K2CO3 (0.036 g, 0.30 mmol). The product
was obtained as a liquid. Yield: 0.170 g, 60%; 1H
NMR (200 MHz, CDCl3): l 1.80–2.10 (m, 3H), 2.20–
2.40 (m, 1H), 3.30–3.50 (m, 2H), 3.60–3.80 (br s, 1H),
3.95–4.10 (m, 1H), 6.40–6.50 (br s, 1H); EIMS: m/z
115 [M+], 97 [M+−18].
3.37. 3-Acetoxy-2-pyrrolidinone 11a
This compound was enzymatically deacylated follow-
ing the procedure described above. The lipase-medi-
ated alcoholysis attained near 51% conversion in 20
h. The products obtained displayed the following
characteristics.

A. Kamal et al. / Tetrahedron: Asymmetry 14 (2003) 2587–2594
2593
3.38. (R)-3-Hydroxy-2-pyrrolidinone 1a
alcoholysis proceeded to 45% conversion in 18 h. The
products obtained displayed the following
characteristics.
[h]2D5=+120.0 (c 1, CHCl3): 1H NMR (200 MHz,
CDCl3): l 1.95–2.20 (m, 1H), 2.40–2.60 (m, 1H), 3.20–
3.35 (m, 2H), 4.25–4.40 (m, 2H), 7.0 (br s, 1H); EIMS:
m/z 101 [M+].
3.47. (R)-3-Hydroxy-1-benzyl-2-pyrrolidinone 1d
[h]2D5=+32.5 (c 1, CHCl3): 1H NMR (200 MHz,
CDCl3): l 1.85–2.00 (m, 1H), 2.30–2.45 (m, 1H), 3.10–
3.30 (m, 2H), 4.35–4.45 (m, 3H), 5.05–5.25 (br s, 1H),
7.15–7.40 (m, 5H); EIMS: m/z 191 [M+].
3.39. (S)-3-Acetoxy-2-pyrrolidinone 11a
[h]2D5=−30.4 (c 1, CHCl3): 1H NMR (200 MHz,
CDCl3): l 1.90–2.20 (m, 4H), 2.30–2.70 (m, 1H), 3.30–
3.50 (m, 2H), 5.20 (t, 1H, J=7.7 Hz), 7.90–8.00 (br s,
1H); EIMS: m/z 100 [M+ −43].
3.48. (S)-3-Acetoxy-1-benzyl-2-pyrrolidinone 11d
[h]2D5=−51.2 (c 1, CHCl3): 1H NMR (200 MHz,
CDCl3): l 1.80–2.00 (m, 1H), 2.10 (s, 3H), 2.50–2.65
(m, 1H), 3.20–3.35 (m, 2H), 4.30 (d, 2H, J=8.5 Hz),
5.20 (t, 1H, J=6.6 Hz), 7.15–7.40 (5H, m); EIMS: m/z
173 [M+ −60] (loss of acetoxy group).
3.40. 3-Acetoxy-1-methyl-2-pyrrolidinone 11b
This compound was enzymatically deacylated following
the procedure described above. The lipase-mediated
alcoholysis attained near 47% conversion in 24 h. The
products
obtained
displayed
the
following
characteristics.
3.49. 3-Acetoxy-2-piperidinone 12a
3.41. (R)-3-Hydroxy-1-methyl-2-pyrrolidinone 1b
This compound was enzymatically deacylated following
the procedure described above. The lipase-mediated
alcoholysis proceeded to 50% conversion in 24 h. The
[h]2D5=+126.5 (c 1, CHCl3): 1H NMR (200 MHz,
CDCl3): l 1.85–2.00 (m, 1H), 2.10–2.20 (m, 1H), 2.90
(s, 3H), 3.20–3.45 (m, 2H), 4.20–4.30 (t, 1H, J=6 Hz);
EIMS: m/z 115 [M+].
products
obtained
displayed
the
following
characteristics.
3.50. (R)-3-Hydroxy-2-piperidinone 2a
3.42. (S)-3-Acetoxy-1-methyl-2-pyrrolidinone 11b
1
[h]2D5=+6.0 (c 1, CHCl3): H NMR (200 MHz, CDCl3):
l 1.80–2.10 (m, 3H), 2.20–2.40 (m, 1H), 3.30–3.50 (m,
2H), 3.60–3.80 (br s, 1H), 3.95–4.10 (m, 1H), 6.40–6.50
(br s, 1H); EIMS: m/z 115 [M+].
[h]2D5=−31.0 (c 1, CHCl3): 1H NMR (200 MHz,
CDCl3): l 1.90–2.10 (m, 4H), 2.30–2.70 (m, 1H), 3.0 (s,
3H), 3.30–3.50 (m, 2H), 5.20 (t, 1H, J=7.0 Hz); EIMS:
m/z 157 [M+].
3.51. (S)-3-Acetoxy-2-piperidinone 12a
3.43. 3-Acetoxy-1-ethyl-2-pyrrolidinone 11c
1
[h]2D5=−1.5 (c 1, CHCl3): H NMR (200 MHz, CDCl3):
This compound was enzymatically deacylated following
the procedure described above. The lipase-mediated
alcoholysis proceeded to 49% conversion in 24 h. The
l 1.70–1.90 (m, 3H), 2.15–2.25 (m, 4H), 3.30–3.45 (m,
2H), 5.2 (t, 1H, J=5 Hz), 7.40 (br s, 1H); EIMS: m/z
157 [M+], 114 [M+−43].
products
obtained
displayed
the
following
characteristics.
3.52. 3-Acetoxy-1-methyl-2-piperidinone 12b
3.44. (R)-3-Hydroxy-1-ethyl-2-pyrrolidinone 1c
This compound was enzymatically deacylated following
the procedure described above. The lipase-mediated
alcoholysis proceeded to 45% conversion in 28 h. The
[h]2D5=+131.0 (c 1, CHCl3); 1H NMR (200 MHz,
CDCl3): l 1.10–1.20 (t, 3H, J=5.5 Hz), 1.90–2.05 (m,
1H), 2.35–2.50 (m, 1H), 3.20–3.50 (m, 4H), 4.15–4.40
(m, 2H); EIMS: m/z 129 [M+].
products
obtained
displayed
the
following
characteristics.
3.45. (S)-3-Acetoxy-1-ethyl-2-pyrrolidinone 11c
3.53. (R)-3-Hydroxy-1-methyl-2-piperidinone 2b
1
[h]2D5=−25.2 (c 1, CHCl3): H NMR (200 MHz, CDCl3)
1H NMR (200 MHz, CDCl3): l 1.80–2.10 (m, 4H),
2.20–2.40 (m, 1H), 3.0 (s, 1H), 3.60–3.80 (s br, 1H),
3.95–4.10 (m, 1H).
l 1.20–1.30 (t, 3H, J=7.7 Hz), 1.85–1.95 (m, 1H), 2.15
(s, 3H), 2.45–2.60 (m, 1H), 3.40–3.60 (m, 4H), 5.2 (t,
1H, J=6.0 Hz); EIMS: m/z 111 [M+ −60] (Loss of OAc
group).
3.54. (S)-3-Acetoxy-1-methyl-2-piperidinone 12b
3.46. 3-Acetoxy-1-benzyl-2-pyrrolidinone 11d
1H NMR (200 MHz, CDCl3): l 1.60–1.80 (m, 3H),
2.00–2.20 (m, 4H), 2.90 (s, 3H), 3.20–3.50 (m, 2H), 5.2
(t, 1H, J=5 Hz); EIMS: m/z 171 [M+].
This compound was enzymatically deacylated following
the procedure described above. The lipase-mediated

2594
A. Kamal et al. / Tetrahedron: Asymmetry 14 (2003) 2587–2594
3.55. 3-Acetoxy-1-ethyl-2-piperidinone 12c
ful to CSIR, New Delhi for the award of Research
Fellowship.
This compound was enzymatically deacylated following
the procedure described above. The lipase-mediated
alcoholysis proceeded to 49% conversion in 28 h. The
References
products
obtained
displayed
the
following
characteristics.
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3.56. (R)-3-Hydroxy-1-ethyl-2-piperidinone 2c
1H NMR (200 MHz, CDCl3): l 1.05–1.25 (t, 3H,
J=5.8 Hz), 1.45–1.70 (m, 1H) 1.70–1.90 (m, 2H), 2.15–
2.25 (m, 1H), 3.30–3.50 (m, 4H), 3.70–3.85 (s br, 1H),
3.90–4.00 (m, 2H).
3. (a) Vedjs, E.; Larsen, S.; West, F. G. J. Org. Chem. 1985,
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3.57. (S)-3-Acetoxy-1-ethyl-2-piperidinone 12c
1H NMR (200 MHz, CDCl3): l 1.10–1.20 (t, 3H,
J=6.4 Hz), 1.80–2.10 (m, 3H), 2.10–2.25 (m, 4H),
3.30–3.50 (m, 4H), 5.2 (1H, t, J=5.6 Hz); EIMS: m/z
185 [M+].
3.58. 3-Acetoxy-1-benzyl-2-piperidinone 12d
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T.; Bravo, A. A. J. Org. Chem. 1990, 55, 3682; (b) Goel,
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This compound was enzymatically deacylated following
the procedure described above. The lipase-mediated
alcoholysis proceeded to 50% conversion in 18 h. The
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obtained
displayed
the
following
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1133; (b) Hamilton, P.; Ortiz, P. Biochemical Preparations
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9. Benley, J. M.; Wadsworth, H. J.; Wills, C. L. J. Chem.
3.59. (S)-3-Acetoxy-1-benzyl-2-piperidinone 12d
[h]2D5=−10.0 (c 1, CHCl3): 1H NMR (200 MHz,
CDCl3): l 1.9–2.10 (m, 3H), 2.1–2.30 (m, 4H), 3.20–3.4
(m, 2H), 4.5 (s, 2H), 5.2 (m, 1H), 7.2 (m, 5H); EIMS:
m/z 206 [M+−43].
3.60. (R)-3-Hydroxy-1-benzyl-2-piperidinone 2d
[h]2D5=+12.0 (c 1, CHCl3): 1H NMR (200 MHz,
CDCl3): l 1.65–1.95 (m, 3H), 2.10–2.30 (m, 1H), 3.10–
3.25 (m, 2H), 3.60–3.90 (br s, 1H), 4.00–4.10 (dd, 1H,
J=4.5 Hz, 7.1 Hz), 4.40–4.70 (dd, 2H, J=13 Hz, 16
Hz), 7.15–7.40 (m, 5H); EIMS: m/z 205[M+].
Soc., Chem. Commun. 1995, 231.
10. Gibbs, G.; Hateley, M. J.; Mclaren, L.; Welham, M.;
Wills, C. L. Tetrahedron Lett. 1999, 40, 1069.
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2001, 66, 997; (b) Kamal, A.; Sandbhor, M.; Ramana, K.
V. Tetrahedron: Asymmetry 2002, 13, 815; (c) Kamal, A.;
Khanna, G. B. R.; Ramu, R. Tetrahedron: Asymmetry
2002, 13, 2039.
Acknowledgements
12. HPLC analysis was performed by using a chiralcel
(Diacel) OD or OJ columns with hexane: 2-propanol
solvent system at 215 nm wavelength and 1 ml min−1 flow
rate.
13. Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J.
Am. Chem. Soc. 1982, 104, 7294.
We are thankful to the Department of Science and
Technology, New Delhi for the financial support for
Grants-in-Aid project under SERC (No. SP/S1/G-47/
99). Two of the authors K.V.R. and A.H.B. are thank-