A facile synthesis of (S)-4-hydroxypyrrolidin-2-one from (S)-malic acid

Article abstract of DOI:10.1055/s-1999-3460

The chiral diol methyl 3,4-dihydroxybutanoate 4b obtained from (S)- malic acid dimethyl ester (3b) was subjected to regioselective tosylation to give the tosylate 6 in good yield. Subsequent treatment of 6 with aqueous ammonia afforded (S)-4hydroxypyrrolidin-2-one (1) through three steps in 32% overall yield from 3b.

Full text of DOI:10.1055/s-1999-3460

SHORT PAPER
745
A Facile Synthesis of (S)-4-Hydroxypyrrolidin-2-one from (S)-Malic Acid
Masahiko Seki, Kazuhiko Kondo*
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima, Yodogawa-ku, Osaka 532-8505, Japan
Fax +81(6)63002816; E-mail: k-kondo@tanabe.co.jp
Received 27 July 1998; revised 30 October 1998
Reduction of the carboxy group of (S)-malic acid b-ethyl
ester (3a) was first attempted to obtain the required chiral
diol 4a. Treatment of 3a with two equivalents of a bo-
rane–methyl sulfide complex,12 however, resulted in a
Abstract: The chiral diol methyl 3,4-dihydroxybutanoate 4b ob-
tained from (S)-malic acid dimethyl ester (3b) was subjected to re-
gioselective tosylation to give the tosylate 6 in good yield.
Subsequent treatment of 6 with aqueous ammonia afforded (S)-4-
hydroxypyrrolidin-2-one (1) through three steps in 32% overall poor yield of the diol 4a with concomitant over-reduction
yield from 3b.
to the triol derivative 5. As an alternative approach, the
use of (S)-malic acid dimethyl ester (3b) was then under-
taken as the starting material. According to the procedure
reported by Saito et al.,13 the desired diol 4b was obtained
in excellent yield (88%) by the treatment of 3b with bo-
rane–methyl sulfide complex in the presence of a catalytic
amount of sodium borohydride. The primary hydroxy
group of 4b was selectively tosylated by the standard pro-
cedure to give the 4-tosyloxy derivative 6 in good yield in
crystals. The subsequent epoxide formation, ring-opening
with ammonia and lactamization were simultaneously
achieved by a simple treatment of 6 with aqueous ammo-
nia to afford the target compound 1 in 51% yield. The
compound 1 synthesized by this method had an optical ro-
tation of [a]D25 –57.8 (c = 1.0, H2O) in good accordance
with the reported value ([a]D25 –55.5 (c = 1.04, H2O)).14
Key words: tosylation, amination, reduction, regioselective reac-
tion
(S)-4-Hydroxypyrrolidin-2-one (1), a component of
Amantia muscaria,1 has recently aroused considerable at-
tention as a cyclic g-aminobutyric acid (GABA) analog2
and as a key precursor for useful compounds such as (S)-
g-amino-b-hydroxybutyric acid (GABOB)3 and the C2
side chains of 1-b-methylcarbapenems.4 There are various
methods available for the synthesis of optically active 4-
hydroxypyrrolidin-2-one which utilize: (2S,4R)-4-hy-
droxyproline as a chiral pool;5 the enzymatic hydroxyla-
tion of pyrrolidine-2-one;6 and asymmetric syntheses.7 Of
more importance is the synthesis involving amination and
cyclization of (S)-4-chloro-3-hydroxybutanoate 28 ob-
tained by enzymatic8,9 or asymmetric reduction10 of the
keto derivative or by microbial dechlorinative resolution
of the racemates11 (Scheme 1). We envisaged the possible
use of the corresponding tosyloxy derivative 6 instead of
the chloride 2 for the reaction (Scheme 2). This would
provide a more simple and practical access to 1 since the
tosylate 6 might be easily obtained from (S)-malic acid via
the regioselective tosylation of the chiral diol 4.
a: Me2S◊BH3, THF (for 3a); Me2S◊BH3, NaBH4 (cat.), THF (for 3b);
b: TosCl, pyridine; c: aq NH3
Scheme 2
In conclusion, a facile synthesis of (S)-4-hydroxypyrroli-
din-2-one (1) was worked out. It required just three steps
from (S)-malic acid dimethyl ester (or four steps from (S)-
malic acid) by the use of a simple procedure and inexpen-
sive reagents. Although the yield of the final step was
moderate,15 the short steps required and the economical
operation make the present synthesis much more advanta-
geous over previously documented methods. The process
Scheme 1
Synthesis 1999, No. 5, 745– 747 ISSN 0039-7881 © Thieme Stuttgart · New York

746
M. Seki, K. Kondo
SHORT PAPER
luted with EtOAc (10 L) and washed with 2 N HCl (2 ¥ 10 L) and
water (10 L), dried (anhyd MgSO4), and then evaporated. The crys-
tals formed were collected by adding hexane to afford 6 (1.69 kg,
72%) as colorless crystals; mp 79–80 °C; [a]D –7.1 (c = 1.0,
CHCl3).
IR (KBr): nmax = 3583, 1743, 1725 cm–1.
1H NMR (CDCl3): d = 2.45 (s, 3 H), 2.53 (d, J = 2 Hz, 1 H), 2.56 (s,
1 H), 3.69 (s, 3 H), 4.03 (s, 1 H), 4.05 (s, 1 H), 4.20–4.31 (m, 1 H),
7.36 (d, J = 8 Hz, 2 H), 7.80 (d, J = 8 Hz, 2 H).
13C NMR (CDCl3): d = 21.7 (q), 37.2 (t), 52.0 (q), 66.0 (d), 72.0 (t),
128.0 (d), 130.0 (d), 132.5 (s), 145.2 (s), 171.9 (s).
has already been applied to multi-kilogram scale prepara-
tion and similar yields were reproduced.
25
IR spectra were recorded on a Perkin–Elmer 1640 IR spectropho-
tometer and are reported as lmax (cm–1). 1H NMR spectra were re-
corded on a Bruker AC-200 (200 MHz) spectrometer and were
reported in d values. MS were taken on a Hitachi M-2000A spec-
trometer at an ionizing potential of 70 eV. Microanalysis were per-
formed by Perkin–Elmer 2400 Series II CHNS/O Analyzer. Flash
chromatography was accomplished by using Kieselgel 60 (230–400
mesh, E. Merck).
SIMS: m/z = 289 (M+ + 1).
Ethyl (S)-3,4-Dihydroxybutanoate (4a)
C12H16O6S
calcd
C
49.98
H
5.59
To a solution of 3a12 (1 g, 6.17 mmol) in THF (10 mL) was added
10 M Me2S◊BH3 in THF (1.23 mL, 12.3 mmol) at 5 °C and the mix-
ture was stirred at 25 °C for 3 h. MeOH (5 mL) was carefully added
to the mixture and evaporated. The residue was purified by column
chromatography (silica gel, hexane/EtOAc 1:1 to 1:3 and then
EtOAc/MeOH 85:15) to give 4a (348 mg, 38%) and triol 5 (222 mg,
34%) both as colorless oil.
(288.326)found
49.91
5.48
(S)-4-Hydroxypyrrolidin-2-one (1)
A mixture of 6 (3 kg, 10.4 mol), concd aq NH3 (24%, 6 kg) and wa-
ter (7.5 L) was warmed up to 70 °C for 30 min and refluxed for 3 h.
The mixture was evaporated, and EtOH (15 L) was added to dis-
solve the residue. The mixture was gradually cooled down to 30 °C
for 1 h and stirred at 5 °C for 1 h. The crystals formed were filtered
off and the solid collected was washed with EtOH (2.88 L). The fil-
trate and washings were combined and evaporated. The residue was
dissolved in water (62 ml) and charged on ion exchange column
(IRA-400, OH– form, 9 L) for 1 h. Developing was carried out for
2.5 h by using water (24 L), and fractions collected were evaporat-
ed. EtOH (2.88 L) was added to the residue and evaporated. The re-
sulting residue was dissolved in EtOH (5.96 L) and cooled down to
30 °C for 1 h and stirred at 5 °C for 1 h. The crystals formed were
collected and washed with cold EtOH (865 mL) to afford 1 (538 g,
51%) as colorless crystals; mp 154–155 °C (lit.14 mp 155–157 °C);
4a:
[a]D25 +6.3 (c = 1.0, CDCl3) (lit.13b [a]D25 +6.22 (c = 1.22, CDCl3))
IR (KBr): nmax = 3365, 1734 cm–1.
1H NMR (CDCl3): d = 1.32 (t, J = 7 Hz, 3 H), 2.48 (dd, J = 4.6, 16
Hz, 1 H), 2.58 (dd, J = 7.8, 16 Hz, 1 H), 2.73 (s, 2 H), 3.54 (dd, J =
6.2, 10 Hz, 1 H), 3.66–3.74 (m, 1 H), 4.19 (q, J = 7 Hz, 2 H).
13C NMR (CDCl3): d = 14.12 (q), 37.90 (t), 60.95 (t), 65.70 (t),
68.75 (d), 172.53 (s).
SIMS: m/z = 149 (M+ + 1).
5:
[a]D25 –25.6 (c = 0.66, MeOH)
20
20
[a]D –57.8 (c = 1.0, H2O) (lit.14 [a]D –55.5 (c = 1.04, H2O) for
IR (Nujol): nmax = 3348, 2940 cm–1.
(S)-isomer and +57.5 (c = 1.40, H2O) for (R)-isomer).
1H NMR (DMSO-d6): d = 1.29–1.67 (m, 2 H), 3.16–3.34 (m, 2 H),
IR (KBr): nmax = 3247, 1674 cm–1.
1H NMR (DMSO-d6): d = 1.93 (dd, J = 2.8, 16 Hz, 1 H), 2.40 (dd,
J = 6.8, 16 Hz, 1 H), 3.02 (dd, J = 0.9, 10 Hz, 1 H), 3.38–3.48 (m, 1
H), 4.27–4.38 (m, 1 H), 5.14 (d, J = 4 Hz, 1 H), 7.54 (br s, 1 H).
3.39–3.60 (m, 3 H), 4.33–4.40 (m, 2 H), 4.46–4.51 (m, 1 H).
13C NMR (DMSO-d6): d = 36.27 (t), 57.57 (t), 65.65 (t), 68.29 (d).
SIMS: m/z = 107 (M+ + 1).
13C NMR (DMSO-d6): d = 40.13 (t), 50.72 (t), 65.86 (d), 175.48 (s).
SIMS: m/z = 102 (M+ + 1).
C4H10O3 calcdC 45.27
(106.124)found 44.99
H
9.50
9.56
C4H7NO2 calcdC 47.52
(101.108)found 47.67
H
6.98
7.16
N
13.85
13.83
Methyl (S)-3,4-Dihydroxybutanoate (4b)13a
To a solution of 3b (1 kg, 6.17 mol) in THF (13.3 L) was added por-
tionwise 10 M Me2S◊BH3 (617 mL) at 20 °C for 30 min and the mix-
ture was stirred at 20 °C for 30 min. NaBH4 (11.7 g, 0.31 mol) was
added at 10 °C and stirred at 10 °C for 30 min and then at 25 °C for
1 h. To the mixture was added EtOH (2.1 L) and TosCl◊H2O (58.5
g, 0.31 mol) and the mixture was stirred at 25 °C for 30 min. The
mixture was evaporated. Into the residue was added a mixture of tol-
uene/EtOH (1:1, 13.3 L) and the mixture was evaporated. Into the
residue was added toluene (10 L) and the solution was evaporated.
The residue was chromatographed (silica gel, 4.2 kg, EtOAc) to af-
ford 4b13a (728 g, 88%) as a colorless oil.
IR (Nujol): nmax = 3380, 1734 cm–1.
1H NMR (CDCl3): d = 2.49 (dd, J = 5, 17 Hz, 1 H), 2.63 (dd, J = 6,
17 Hz, 1 H), 3.08 (s, 2 H), 3.53 (dd, J = 6, 12 Hz, 1 H), 3.70 (dd, J
= 3.4, 12 Hz, 1 H), 3.72 (s, 3 H), 4.08–4.20 (m, 1 H).
Acknowledgement
The authors extend their hearty thanks to Drs. K. Matsumoto and T.
Iwasaki of this company for their advice and encouragement during
this work.
References
(1) Matsumoto, T.; Trueb, W.; Gwinner, R.; Eugster, C. H. Helv.
Chim. Acta 1969, 52, 716.
(2) Banfi, S.; Fonio, W.; Allievi, E.; Pinza, M.; Dorigotti, L. Far-
maco. Ed. Sci. 1984, 39, 16.
(3) For example, see: Jung, M. E.; Shaw, T. J. J. Am. Chem. Soc.
1980, 102, 6304 and references cited therein.
(4) Miyauchi, M.; Endo, R.; Hisaoka, M.; Yasuda, H.; Kawa-
moto, I. J. Antibiot. 1997, 50, 429.
SIMS: m/z = 135 (M+ + 1).
Iwasaki, T.; Kondo, K.; Horikawa, H.; Yamaguchi, T.; Mat-
sushita, T. US Patent 5153187, Oct. 6, 1992.
(5) Haeusler, J. Monatsh. Chem. 1987, 118, 865.
(6) Srairi, D.; Maurey, G. Bull. Soc. Chim. Fr. 1987, 297.
Methyl (S)-3-Hydroxy-4-(tosyloxy)butanoate (6)
To a solution of 4b13a (1.1 kg, 8 mol) in pyridine (5 L) was added
TosCl (1.72 kg, 9 mol) in one portion at 10 °C and the mixture was
allowed to warm to 25 °C and stirred for 17 h. The mixture was di-
Synthesis 1999, No. 5, 745– 747 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
A Facile Synthesis of (S)-4-Hydroxypyrrolidin-2-one from (S)-Malic Acid
747
(7) Pellegata, R.; Dosi, I.; Villa, M.; Lesma, G.; Palmisano, G.Te-
trahedron 1985, 41, 5607.
Orena, M.; Porzi, G.; Sandri, S. J. Chem. Res. (S) 1990, 376.
(8) Santaniello, E.; Casati, R.; Milani, F. J. Chem. Res. (S) 1984,
132.
(9) Zhou, B.; Gopalan, A. S.; VanMiddlesworth, F.; Shieh, W-R.;
Sih, C. J. Am. Chem. Soc. 1983, 105, 5925.
Shimizu, S.; Kataoka, M.; Morishima, A.; Katoh, M.; Morika-
wa, T.; Miyoshi, T.; Yamada, H. Biotechnology Lett. 1990,
12, 593.
(12) Two equiv of Me2S◊BH3 were necessary to consume all of the
carboxylic acid 3a as described in the literature: Papageor-
gious, C.; Benezra, C. J. Org. Chem. 1985, 50, 1145.
(13) (a) Saito, S.; Hasegawa, T.; Inaba, M.; Nishida, R.; Fujii, T.;
Nomizu, S.; Moriwake, T. Chem. Lett. 1984, 1389.
(b) Saito, S.; Ishikawa, T.; Kuroda, A.; Koga, K.; Moriwake,
T. Tetrahedron 1992, 48, 4067.
(14) Pellegata, R.; Pinza, M.; Pifferi, G. Synthesis 1978, 614.
(15) The yield (51%) is similar to that reported for the correspon-
ding chloride 2 (50%).8
(10) Kitamura, M.; Ohkuma, T.; Takaya, H.; Noyori, R. Tetrahe-
dron Lett. 1988, 29, 1555.
(11) Suzuki, T.; Idogaki, H.; Kasai, N. Tetrahedron: Asymmetry
1996, 7, 3109.
Article Identifier:
1437-210X,E;1999,0,05,0745,0747,ftx,en;F06398SS.pdf
Synthesis 1999, No. 5, 745– 747 ISSN 0039-7881 © Thieme Stuttgart · New York