Efficient syntheses of (S)-4-hydroxy-2-pyrrolidinone derivatives

Article abstract of DOI:10.3987/COM-99-8689

Efficient syntheses of (S)-4-hydroxy-2-pyrrolidinone ((5)-2) and (R)4- acetylthio-2-pyrrolidinone (S), which are key intermediates of oral carbapenem CS-834, were studied. The most efficient route to (S)-2 from (S)- 3-hydroxybutyrolactone (8) was accomplished in high yield via (S)-N-allyl-3- (1-ethoxy)ethoxy-4-hydroxybutyramide (14).

Full text of DOI:10.3987/COM-99-8689

HETEROCYCLES, Vol.53, No.1, 2000, pp. 173 - 181, Received, 5th July, 1999
EFFICIENT SYNTHESES OF (S)-4-HYDROXY-2-PYRROLIDINONE
DERIVATIVES
Osamu Kanno, Masao Miyauchi, and Isao Kawamoto*
Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd.
1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
Abstract – Efficient syntheses of (S)-4-hydroxy-2-pyrrolidinone ((S)-2) and (R)-
4-acetylthio-2-pyrrolidinone (5), which are key intermediates of oral
carbapenem CS-834, were studied. The most efficient route to (S)-2 from (S)-3-
hydroxybutyrolactone (8) was accomplished in high yield via (S)-N-allyl-3-(1-
ethoxy)ethoxy-4-hydroxybutyramide (14).
Since 1β-methylcarbapenem was found to enhance renal dehydropeptidase-I (DHP-I) stability compared
to 1-H carbapenem,1 parenteral and oral 1β-methylcarbapenems have been extensively studied.2 In a
preceding paper,3 we described that a novel oral 1β-methylcarbapenem, CS-834 (1), showed excellent
antibacterial activity and high DHP-I stability. Moreover, it was interesting that CS-834 was chemically
more stable than cephalosphorins in phosphate buffer solution (pH 6.86).4 CS-834 is undergoing phase II
clinical trials as the first oral carbapenem in the world. So we focused our attention on the synthesis of the
CS-834 side chain intermediate (S)-4-hydroxy-2-pyrrolidinone ((S)-2) which was known as cyclic γ-
aminobutiric acid (GABA) analog.5 Several methods for the synthesis of optically active compound ((S)-
2) were studied, which involved amination and cyclization6a,b of ethyl (S)-4-chloro-3-hydroxybutanoate
obtained by enzymatic6b or asymmetric reduction7a of the keto derivative or by microbial optical
resolution.7b A novel method using (S)-malic acid dimethyl ester8 as stating material were reported very
recently. In this paper, we describe efficient syntheses of the key intermediates, (S)-4-hydroxy-2-
pyrrolidinone ((S)-2) and (R)-4-acetylthio-2-pyrrolidinone (5).
OH
H
H
N
O
O
O
S
NH
AcS
NH
HO
NH
O
t
COOCH OCO Bu
2
(S)-2
5
CS-834 (1)
Two methods using optical resolution of racemic compounds and chiral starting material were
investigated. An optical resolution method was employed first. Racemic 4-hydroxy-2-pyrrolidinone (rac-

2) was prepared from 4-amino-3-hydroxybutyric acid (rac-3) by Pellegata’s method9 using
hexamethyldisilazane in xylene in the presence of a catalytic amount of chlorotrimethylsilane followed
by acidic hydrolysis (Scheme 1). Rac-2 was converted into (+)-10-camphorsulfonate (4: diastereomeric
mixture) and then recrystallization of 4 from ethyl acetate gave the desired optically pure isomer (S)-4 in
17% yield. Treatment of (S)-4 with potassium thioacetate afforded (R)-4-acetylthio-2-pyrrolidinone (5) in
76% yield. Overall yield of 5 from 3 was 10% in five steps.
Scheme 1
O
O
OH
a, b
c, d
H N
2
COOH
O
NH
SO
2
HO
NH
rac-2
O
rac-3
4
O
e
AcS
NH
5
Reagents; a) hexamethyldisilazane, TMSCl (cat), reflux in xylene, 8 h; b) 1N-HCl; c) (1S)-(+)-10-camphor-
sulfonyl chloride; d) recrystallization from EtOAc; e) AcSK / MeCN.
Scheme 2
OH
OH
OH
b, c
a
Cl
CN
Cl
CONH
H N
2
COOH
2
6
7
(S)-3
O
O
d, e
f, g
AcS
NH
HO
NH
(S)-2
5
Reagents; a) H2O2 / 2 M aq. NaOH; b) 29% aq. NH3 in a sealed tube, 120 oC, 8 h; c) ion-excahnge resin IRA-120
(H+); d) hexamethyldisilazane, TMSCl (cat), reflux in xylene, 8 h; e) 1N-HCl; f) MsCl / pyridine; g) AcSK / MeCN.
Next, more versatile synthetic routes using chiral starting material were examined. At first, a more
efficient method of preparation of optically pure 3 was investigated as shown in Scheme 2, because the
optical resolution of rac-3 using tartaric acid was very low yield and not suitable for large scale
preparation. Commercially available (S)-4-chloro-3-hydroxybutyronitrile (6) was converted into amide
compound (7) in 55% yield by oxidative hydrolysis. Amination of 7 with aqueous ammmonia and
subsequent hydrolysis with ion exchange resin (acid form) gave optically pure (S)-4-amino-3-

hydroxybutyric acid ((S)-3) in 80% yield. The conversion of (S)-3 into (S)-2 was achieved in 88% yield
by Pellegata’s method.9 Mesylation of (S)-2 followed by treatment with potassium thioacetate in
acetonitrile gave thioacetate (5) in 57% yield. The whole conversion yield from 6 to 5 was 22% using this
route.
Scheme 3
O
OR
O
b
a
HO
CONHR'
HO
O
RO
O
8
11 R= TBS
13 R= EE
14 R= EE
R'= Bn
R'= Bn
R'=Allyl
9
R= TBS
R= 1-ethoxyethyl (EE)
10
O
O
OH
e or f
c, d
RO
NR'
TBSO
CONHBn
HO
NH
12
(S)-2
15 R= TBS
16 R= EE
17 R= EE
R'= Bn
R'= Bn
R'=Allyl
Reagents; a) 9: TBSCl, imidazole / DMF, 60 oC, 2 h; 10: ethyl vinyl ether, PPTS / CH2Cl2, rt; b) 11 and 13: benzylamine
50 oC, 2 h, neat; 14: allylamine, 40 oC, 4 h, neat; c) MsCl, Et3N / THF, 0 oC; d) KN(TMS)2, 18-crown-6 (0.2 eq) /
THF, -78 oC or NaH, 18-crown-6 (0.2 eq) / DMF, rt; e) Li, liq. NH3, -70 oC, then 0.1M HCl-MeOH; f) RhCl3・3H2O
(2 mol%), reflux in EtOH, 2 h, then reflux in AcOH-H2O (1:1), 22 h.
On the other hand, another route using commercially available (S)-3-hydroxy-γ-butyrolactone (8) was
studied as shown in Scheme 3. The protection of 8 with t-butyldimethylchlorosilane (TBSCl) or ethyl
vinyl ether gave protected lactones (9) and (10) in 99 and 100% yields, respectively. The ring cleavages
of 9 and 10 with benzylamine or allylamine afforded amide compounds (11, 13 and 14) in 83, 92 and
92% yields, respectively. In the case of the silyl ether compound (9), a considerable amount of silyl
migration to the 4-hydroxy group was observed to give a 4-silyl compound (12) in 15% yield. Mesylation
of 11, 13 and 14 led to corresponding mesylate and successive cyclization of mesylates using sodium
hydride or potassium bis(trimethylsilyl)amide (KN(TMS)2) in the presence of a catalytic amount of 18-
crown-6 afforded γ-lactams (15, 16 and 17) in 91, 88 and 84% yields, respectively. The final step in this
route was deprotection of the N- and O-protecting groups. Deprotection of the benzyl group of 16 with Li
in liquid NH3 and subsequent acidic hydrolysis led to (S)-4-hydroxy-2-pyrrolidinone ((S)-2) in 72% yield.
N-Allyl compound (17) was treated with RhCl3・3H2O in ethanol and successive acidic hydrolysis in
aqueous AcOH afforded (S)-2 in 80% yield. In the case of the N-allyl and O-1-ethoxyethyl protecting
groups, the most effective conversion from 8 to (S)-2 was accomplished via 14 and 17 in 65% overall
yield.

In summary, the most efficient route for (S)-4-hydroxy-2-pyrrolidinone ((S)-2), which is a key
intermediate of oral carbapenem CS-834, was achieved in 65% overall yield from (S)-3-
hydroxybutyrolactone (8).
EXPERIMENTAL
General Methods
IR spectra were recorded on a Jasco FT-IR 8300 or 8900 spectrophotometer. NMR spectra were recorded
on JEOL EX 270 (270 MHz) or GSX-400 (400 MHz) spectrometer using tetramethylsilane (TMS) or
sodium 3-(trimethylsilyl)propionate-d4 (TSP-d4) as an internal standard. The melting point was
determined using a Yanagimoto micro-melting point apparatus and was not corrected. Optical rotations
were obtained with a Jasco DIP-370 polarimeter. Column chromatography was carried out on silica gel
60 (230-400 mesh, Art.9385, Merck) or Cosmosil 75C18 PREP (75 µm, Nacalai Tesque, Inc.).
Preparation of (R)-4-acetylthio-2-oxopyrrolidine (5) from 4-amino-3-hydroxybutyric acid (rac-3)
i) 4-Hydroxy-2-oxopyrrolidine (rac-2)
4-Hydroxy-2-oxopyrrolidine (rac-2) was prepared in 96% yield as crystals according to the following
Pellegata’s method.9
To a suspension of rac-3 (5.0 g, 42.0 mmol) in xylene (100 mL), hexamethyldisilazane (10.2 g, 62.9
mmol) and trimethylsilyl chloride (100 µL) were added at rt, and then the mixture was refluxed for 8 h.
The reaction mixture was evaporated. The crystals were collected and washed with xylene and
diisopropyl ether to afford the trimethylsilyl (TMS) ether of rac-2 (6.18 g, 85%) as colorless crystals. To a
solution of TMS ether of rac-2 (3.52 g, 20.3 mmol) in MeCN (31.5 mL), water (3.5 mL) and 1N-HCl (35
µL) was added at rt and the mixture was stirred for 0.5 h at the same temperature. After evaporation of the
mixture and azeotopic removal of trace of water twice with EtOH, the residue was crystallized from
EtOH. Resulting crystals were collected and washed with cooled EtOH to afford rac-2 (1.97 g, 96%) as
1
colorless crystals. mp 117-118 °C H NMR (400 MHz, D2O) δ 2.28 (1H, dd, J = 17.7, 1.6 Hz), 2.77
(1H, dd, J = 17.7, 6.7 Hz), 3.34 (1H, dd, J = 11.8, 1.0 Hz), 3.72 (1H, dd, J = 11.8, 5.2 Hz), 4.60-4.64
(1H, m).
ii) (S)-4-[(1S)-10-Camphorsulfonyloxy]-2-oxopyrrolidine (4)
To a solution of rac-2 (1.01 g, 10 mmol) in pyridine (50 mL) was added (1S)-(+)-10-camphorsulfonyl
chloride (2.63 g, 10.5 mmol) at 0°C, and then the mixture was stirred for 0.5 h at rt. After this mixture
was evaporated, the residue was diluted with ethyl acetate. The organic layer was washed twice with
brine and dried over Na2SO4 and evaporated in vacuo. The residue was purified by silica gel column
chromatography (EtOAc-MeOH 9:1) to give 4 as a crude product. The crude product was recrystallized
from EtOAc-MeOH (95:5) to afford the single isomer 4 (262 mg, 17%) as colorless crystals. mp 114-
116 °C; 1H NMR (270 MHz, CDCl3) δ 0.87 (3H, s), 1.10 (3H, s), 1.47 (1H, ddd, J = 12.7, 9.2, 3.9 Hz),
1.70 (1H, ddd, J = 9.2, 4.6, 3.9 Hz), 1.97 (1H, d, J = 18.5 Hz), 2.00-2.18 (2H, m), 2.33-2.51(2H, m),

2.63 (1H, dd, J = 18.2, 2.6 Hz), 2.80 (1H, dd, J = 18.2, 6.6 Hz), 3.05 (1H, d, J = 14.8 Hz), 3.52 (2H, d,
J = 14.8 Hz), 3.66 (1H, dd, J = 11.9, 1.0 Hz), 3.83 (1H, dd, J = 11.9, 6.0 Hz), 5.41-5.49 (1H, m), 6.01
(1H, s). Anal. Calcd for C14H21NO5S: C 53.32, H 6.71, N 4.44, S 10.17. Found: C 53.26, H 6.68, N 4.24, S
10.35.
iii) (R)-4-Acetylthio-2-oxopyrrolidine (5)
To a solution of 4 (160 mg, 0.507 mmol) in acetonitrile (5 mL) was added potassium thioacetate (90 mg,
0.788 mmol) and then the mixture was refluxed for 5 h. After insoluble materials were removed by
filtration, the filtrate was evaporated in vacuo. The residue was purified by silica gel column
chromatography (EtOAc-MeOH 97:3) to afford 5 (61 mg, 76%) as crystals. mp 58-59 °C; [α]D25 +45.0° (c
1.13, MeOH); IR (KBr) cm-1 1689, 1125; 1H NMR (400 MHz, CDCl3) δ 2.30 (1H, dd, J = 17.4, 6.0 Hz),
2.35 (3H, s), 2.80 (1H, dd, J = 17.4, 9.1 Hz), 3.31 (1H, dd, J = 10.2, 5.1 Hz), 3.89 (1H, dd, J = 10.2, 7.2
Hz), 4.15-4.23 (1H, m), 7.27 (1H, br s). Anal. Calcd for C6H9NO2S: C 45.27, H 5.77, N 8.80, S 20.14.
Found: C 45.18, H 5.81, N 8.84, S 20.22.
Preparation of (R)-4-acetylthio-2-oxopyrrolidine (5) from (S)-4-chloro-3-hydroxybutyronitrile (6)
i) (S)-4-Chloro-3-hydroxybutyramide (7)
To a 35% H2O2 aqueous solution (32 mL) was added 6 (5.0 g, 41.8 mmol) at 0°C and then the mixture
was stirred for 3 h at the same temperature. The pH of the mixture was adjusted to 8.5 with 2M aqueous
NaOH. After an excess amount of H2O2 was decomposed with MnO2, the insoluble materials were
removed by filtration and the filtrate was evaporated in vacuo. The residue was purified by silica gel
column chromatography (EtOAc-MeOH 97:3) to afford 7 (3.15 g, 55%) as crystals. mp 69-71 °C; IR
(KBr) cm-1 3370, 3192; 1656, 1434, 1407, 1113; 1H NMR (400 MHz, D2O) δ 2.53 (1H, dd, J = 14.8, 8.1
Hz), 2.59 (1H, dd, J = 14.8, 4.9 Hz), 3.63 (1H, dd, J = 11.7, 5.9 Hz), 3.73 (1H, dd, J = 11.7, 4.0 Hz), 4.26-
4.34 (1H, m), 7.27 (1H, br s). Anal. Calcd for C4H8NO2Cl: C 34.92, H 5.86, N 10.18, Cl 25.77. Found: C
34.56, H 5.90, N 10.01, Cl 25.97.
ii) (S)-4-Amino-3-hydroxybutyric acid ((S)-3)
To a solution of 7 (9.5 g, 69 mmol) in water (48 mL) was added 29% aqueous NH3 (475 mL) over 30 min
at rt and then the mixture was stirred for 18 h at the same temperature. After the solvent was evaporated,
the residue was dissolved in water (400 mL). The aqueous solution was loaded onto an Amberlite IRA-
120B column (H+ form, 200 mL) and the column was washed with 500 mL more of water to remove HCl.
This resin was heated to 68 °C for 9 h and after washing with water (200 mL), the column was eluted
with 2 M aqueous NH3 (700 mL). This eluent was evaporated in vacuo and the resulting residue was
recrystallized from MeOH-water (4:1) to afford (S)-3 (6.58 g, 80%) as colorless crystals. mp 224-226 °C
(lit.,10 214 °C ); [α]D25 +19.8° (c 2.27, H2O) (lit.,10 [α]D22 +20.1° (c 1.7, H2O)); IR (KBr) cm-1 3149, 2862,
1
2757, 2190, 1660, 1576, 1390, 1338, 1055; H NMR (400 MHz, D2O) δ 2.45 (1H, d, J = 6.6 Hz), 2.97
(1H, dd, J = 13.1, 9.4 Hz), 3.18 (1H, dd, J = 13.1, 3.0 Hz), 4.22 (1H, ddd, J = 9.4, 6.6, 3.0 Hz). Anal.
Calcd for C4H9NO3: C 40.33, H 7.62, N 11.76. Found: C 40.07, H 7.54, N 11.86.

iii) (S)-4-Hydroxy-2-oxopyrrolidine ((S)-2)
Using Pellegata’s method,9 (S)-2 (5.4 g, >99% ee) was prepared from (S)-3 (7.3 g, 61.3 mmol) in 88%
yield. The ee of (S)-2 was determined by HPLC analysis. The retention time of (S)-2 was 75.4 min on a
CHILALPAK AD (4.6 mmφ x 250 mm; eluent: n-hexane – EtOH 95:5; flow rate: 1 mL/min.; detection;
25
UV, 220 nm), The retention time of (R)-2 was 69.2 min under the same condition. mp 158-161 °C; [α]D
-54.2° (c 1.00, H2O); IR (KBr) cm-1 3247, 3145, 1672, 1483, 1446, 1416. Anal. Calcd for C4H7NO2: C
40.33, H 7.62, N 11.76. Found: C 40.07, H 7.54, N 11.86.
iv) (R)-4-Acetylthio-2-oxopyrrolidine (5)
To a solution of (S)-2 (1.90 g, 18.8 mmol) in pyridine (100 mL) was added dropwise methanesulfonyl
chloride (2.26 g, 19.7 mmol) under ice-cooling. The mixture was stirred at rt for 1.5 h, and then the
mixture was concentrated by evaporation under reduced pressure. Saturated aqueous NaHCO3 was then
added to the mixture and the mixture was concentrated by evaporation under reduced pressure. A mixture
of EtOAc-MeOH (1:1) was then added to the resulting residue. The insoluble portion was removed by
filtration and the filtrate was concentrated by evaporation under reduced pressure. The residue was
chromatographed on silica gel column with EtOAc-MeOH (9:1 to 4:1) as eluent to give a crystalline
powder. The powder was recrystallized from EtOAc-MeOH to afford (S)-4-methanesulfonyloxy-2-
25
pyrrolidinone (2.44 g, 72%) as crystals. mp 137-139 °C. [α]D –35.5° (c 1.09, MeOH). IR (KBr) cm-1
1719, 1697, 1659, 1305, 1177, 1171, 1159, 963. 1H NMR (400 MHz, DMSO-d6) δ 2.28 (1H, dd, J = 17.6,
1.8 Hz), 2.71 (1H, dd, J = 17.6, 6.3 Hz), 3.24 (3H, s), 3.37 (1H, d, J = 11.9 Hz), 3.66 (1H, dd, J = 11.9,
5.3 Hz), 5.31-5.34 (1H, m), 7.85 (1H, br s).
To a solution of (S)-4-methanesulfonyloxy-2-pyrrolidinone (896 mg, 5.00 mmol) in acetonitrile (90 mL)
was added potassium thioacetate (857 mg, 7.50 mmol) and the mixture was then refluxed for 2 h. The
insoluble material was removed by filtration and the filtrate was concentrated by evaporation under
reduced pressure. The residue was chromatographed on silica gel column with EtOAc-MeOH (96:4) as
the eluent to give a powder. The powder was recrystallized from EtOAc-cyclohexane to give 5 as crystals
(455 mg, 57%). mp 59-60 °C. [α]D25 +47.3° (c 1.33, MeOH). IR (KBr) cm-1 1689, 1125. Anal. Calcd for
C6H9NO2S: C 45.27, H 5.70, N 8.80, S 20.14. Found: C 45.23, H 5.62, N 8.82, S 19.51.
Preparation of (S)-4-hydroxy-2-oxopyrrolidine ((S)-2) from (S)-3-hydroxy-γ-butyrolactone (8)
(S)-3-t-Butyldimethylsilyloxy-γ-butyrolactone (9)
To a solution of (S)-3-hydroxy-γ-butyrolactone (8) (2.0 g, 19.6 mmol) and imidazole (10.7 g, 157 mmol)
in dimethylformamide (100 mL) was added the solution of t-butyldimethylsilyl chloride (8.86 g, 58.8
mmol) in dimethylformamide (10 mL) and then the mixture was stirred for 2 h at 60 °C. The mixture was
evaporated under reduced pressure to give an oily residue. After the residue was diluted with EtOAc, the
organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by silica gel column chromatography with hexane-
EtOAc (9:1) to afford 9 (4.19 g, 99%) as a colorless powder. [α]D25 –46.4° (c 2.28, MeOH), IR (KBr) cm-1

2959, 1759, 1181, 1094, 998. 1H NMR (270 MHz, CDCl3) δ 0.09 (6H, s), 0.89 (9H, s), 2.44 (1H, dd, J
= 17.8, 2.6 Hz), 2.69 (1H, dd, J = 17.8, 5.9 Hz), 4.18 (1H, dd, J = 9.9, 2.6 Hz), 4.38(1H, dd, J = 9.6, 5.0
Hz), 4.59-4.62(1H, m). Anal. Calcd for C10H20O3Si: C 55.52, H 9.32. Found: C 55.45, H 9.37.
(S)-3-(1-Ethoxy)ethoxy-γ-butyrolactone (10)
To a solution of (S)-3-hydroxy-γ-butyrolactone (8) (2.0 g, 19.6 mmol) in CH2Cl2 (40 mL) was added
pyridinium p-toluenesufonate (246 mg, 0.196 mmol) and ethyl vinyl ether (7.06 g, 98.0 mmol) at rt. The
mixture was concentrated under reduced pressure and the residual oil was purified by silica gel column
chromatography with hexane-EtOAc (1:2) as the eluent to afford 10 (3.41 g, 100%) as an oil. IR (CHCl3)
cm-1 2981, 1783, 1376, 1172. 1H NMR (400 MHz, CDCl3) δ 1.20 (3H, t, J = 7.0 Hz), 1.32 (1/2H, d, J =
2.2 Hz), 1.32 (1/2H, d, J = 2.6 Hz), 2.54-2.62 (1H, m), 2.68-2.77 (1H, m), 3.44-3.53 (1H, m), 3.54-3.64
(1H, m), 4.28-4.34 (1H, m), 4.39 (1H, dd, J = 10.1, 5.2 Hz), 4.44 (1H, dd, J = 9.8, 5.4 Hz), 4.56-4.61 (1H,
m), 4.76 (1H, q, J = 5.4 Hz), 4.79 (1H, q, J = 5.7 Hz). Anal. Calcd for C8H14O4: C 55.16, H 8.10. Found: C
55.00, H 8.29.
(S)-N-Benzyl-3-t-butyldimethylsilyloxy-4-hydroxybutyramide (11)
(S)-N-Benzyl-4-t-butyldimethylsilyloxy-3-hydroxybutyramide (12)
To γ-lactone (9) (500 mg, 2.31 mmol) was added benzylamine (980 mg, 9.15 mmol) at rt and then the
mixture was stirred for 2 h at 50 °C. The reaction mixture was purified by silica gel column
chromatography with hexane-EtOAc (1:1) as the eluent to afford 11 (622 mg, 83%) and 12 (115 mg,
15%) as a viscous oil.
11: [α]D25 –4.7° (c 1.12, CHCl3), IR (liquid film) cm-1 3306, 2929. 1648, 1547, 1254, 1114, 837, 779. 1H
NMR (270 MHz, CDCl3) δ 0.08 (3H, s), 0.09(3H, s), 0.85 (9H, s), 2.28 (1H, t, J = 5.8 Hz), 2.49 (2H, d, J
= 5.6 Hz), 3.45-3.51 (2H, m), 4.17-4.25 (1H, m), 4.34 (1H, dd, J = 14.6, 5.3 Hz), 4.52(1H, dd, J = 14.6,
6.0 Hz), 6.15 (1H, br), 7.25-7.37 (5H, m). MS (m/z) 323 [M+].
1
12: IR (liquid film) cm-1 3307, 2929, 1648, 1549, 1254, 1122, 837, 779. H NMR (270 MHz, CDCl3) δ
0.06 (6H, s), 0.89 (9H, s), 2.35-2.47 (2H, m), 3.30 (1H, d, J = 3.8 Hz), 3.53 (1H, dd, J = 10.0, 6.5 Hz),
3.61 (1H, dd, J = 10.0, 4.8 Hz), 3.98-4.12 (1H, m), 4.46 (2H, d, J = 5.8 Hz), 6.50 (1H, br), 7.21-7.41 (5H,
m); MS m/z: 323 [M+].
(S)-N-Benzyl-3-(1-ethoxy)ethoxy-4-hydroxybutyramide(13)
To γ-lactone (10) (1.0 g, 5.74 mmol) was added benzylamine (1.23 g, 11.5 mmol) at rt and then the
mixture was stirred for 2 h at 50 °C. The reaction mixture was purified by silica gel column
chromatography with EtOAc as the eluent to afford 13 (1.48 g, 92%) as a viscous oil. IR (CHCl3) cm-1
1
3446, 2985, 1668, 1518, 1054, 964; H NMR (400 MHz, CDCl3) δ 1.13 -1.32 (6H, m), 2.33-2.58 (2H,
m), 3.41-3.69 (4H, m), 4.09-4.15 (1H, m), 4.37-4.51 (2H, m), 4.68 (1/2H, q, J = 5.2 Hz), 4.79 (1/2H, q, J
= 5.3 Hz), 6.09 (1/2H, br), 6.60 (1/2H, br), 7.26-7.35 (5H, m). Anal. Calcd for C15H23NO4: C 64.04, H
8.24, N 4.98. Found: C 63.65, H 8.23, N 4.94.

(S)-N-Allyl-3-(1-ethoxy)ethoxy-4-hydroxybutyramide (14)
To γ-lactone 10 (850 g, 4.88 mmol) was added allylamine (557 mg, 9.76 mmol) at rt and then the mixture
was stirred for 4 h at 40 °C. The reaction mixture was purified by silica gel column chromatography with
EtOAc-MeCN (5:1 to 4:1) as the eluent to afford 14 (1.04 g, 92%) as a viscous oil. IR (CHCl3) cm-1 3450,
1
2989, 1668, 1519, 1127, 1093, 1054; H NMR (400 MHz, CDCl3) δ 1.22 (3/2H, t, J = 7.3 Hz), 1.23
(3/2H, t, J = 7.3 Hz), 1.31 (3/2H, d, J = 5.2 Hz), 1.35 (3/2H, d, J = 5.3 Hz), 2.46-2.56 (1H, m), 2.60 (1H, t,
J = 6.3 Hz), 2.58-2.70 (1H, m), 3.48-3.74 (4H, m), 3.79 (3H, s), 4.14-4.20 (1H, m), 4.75 (1/2H, q, J = 5.2
Hz), 4.86 (1/2H, q, J = 5.2 Hz), 6.34-6.87 (2H, m), 7.38-7.45 (2H, m). Anal. Calcd for C11H21O4N: C
57.12, H 9.15, N 6.06. Found: C 56.84, H 9.56, N 5.83.
(S)-N-Benzyl-4-t-butyldimethylsilyloxy-2-oxopyrrolidine (15)
To a solution of 11 (100 mg, 0.309 mmol) in THF (2 mL) was added triethylamine (47 mg, 0.464 mmol)
and methanesulfonyl choloride (46 mg, 0.402 mmol) at 0oC, and then the mixture was stirred for 0.5 h at
the same temperature. The precipitates were removed by filtration and washed with THF (3mL). To the
filtrate was added 18-crown-6 (16 mg, 0.062 mmol) and 55% NaH (15 mg, 0.618 mol, hexane-washed) at
0oC and the mixture was stirred for 4 h at rt. The reaction mixture was quenched with saturated aqueous
NH4Cl and diluted with EtOAc (30 mL). The organic layer was washed with brine, dried over Na2SO4 and
concentrated under reduced pressure. The residue was purified by silica gel column chromatography with
20
hexane-EtOAc (3:2) as the eluent to afford 15 (95 mg, 91%) as an oil. [α]D +7.7° (c 0.58, MeOH), IR
1
(CHCl3) cm-1 2957, 2932, 2858, 1682, 1336, 1096, 1006, 838; H NMR (270 MHz, CDCl3) δ 0.05 (6H,
s), 0.85 (9H, s), 2.40 (1H, dd, J = 16.9, 3.3 Hz), 2.67 (1H, dd, J = 17.0, 6.4 Hz), 3.12 (1H, dd, J = 10.4, 2.8
Hz), 3.45 (1H, dd, J = 10.4, 5.9 Hz), 4.37(1H, d, J = 15.1 Hz), 4.41-4.53 (1H, m), 4.59 (1H, d, J = 15.1
Hz), 7.22-7.39 (5H, m). Anal. Calcd for C17H27NO2Si: C 66.84, H 8.91, N 4.59. Found: C 66.44, H 8.99,
N 4.57.
When potassium bis(trimethylsilyl)amide was used, after the filtration, the mesylate intermediate was
treated with 1.3 eq. potassium bis(trimethylsilyl)amide for 1 h in THF at –78 °C (96% yield).
(S)-N-Benzyl-4-(1-ethoxy)ethoxy-2-oxopyrrolidine (16)
By a similar manner as that described for the preparation of 15 from 11, 16 (124 mg, 88%) was prepared
1
as an oil from 13 (150 mg, 0.533 mmol). IR (CHCl3) cm-1 2993, 2933, 1683, 1443, 1265, 1128, 838; H
NMR (400 MHz, CDCl3, TMS) δ 1.14 (3/2H, t, J = 7.0 Hz), 1.17 (3/2H, t, J = 7.0 Hz), 1.27 (3/2H, d, J =
5.1 Hz), 1.28 (3/2H, d, J = 4.6 Hz), 2.50 (1/2H, dd, J = 17.0, 4.0 Hz), 2.54 (1/2H, dd, J = 17.0, 3.9 Hz),
2.69 (1/2H, dd, J = 17.1, 7.3 Hz), 2.73 (1/2H, dd, J = 17.3, 7.3 Hz), 3.19-3.28 (1H, m), 3.35-3.59 (3H, m),
4.38-4.54 (3H, m), 4.67-4.74 (1H, m), 7.23-7.35 (5H, m). MS m/z: 264 [M+H]+.
(S)-N-Allyl-4-(1-ethoxy)ethoxy-2-oxopyrrolidine (17)
By a similar manner as that described for the preparation of 15 from 11, 17 (77 mg, 84%) was prepared as
1
an oil from 14 (100 mg, 0.432 mmol). IR (CHCl3) cm-1 2991, 2915, 1683, 1444, 1269, 1128; H NMR
(400 MHz, CDCl3) δ 1.20 (3H, t, J = 7.2 Hz), 1.31 (3H, d, J = 5.4 Hz), 2.46 (1/2H, dd, J = 17.3, 4.0 Hz),

2.60 (1/2H, dd, J = 17.4, 4.0 Hz), 2.66 (1/2H, dd, J = 14.8, 7.3 Hz), 2.70 (1/2H, dd, J = 15.0, 7.3 Hz),
3.29-3.36 (1H, m), 3.44-3.64 (3H, m), 3.84-3.98 (2H, m), 4.41-4.47 (1H, m), 4.73-4.78 (1H, m), 5.18-
5.23 (2H, m), 5.68-5.78 (1H, m). MS m/z: 214 [M+H]+.
(S)-4-Hydroxy-2-oxopyrrolidine ((S)-2) from 16
Liquid NH3 (ca.10 mL) was trapped in the solution of 16 (250 mg, 0.949 mmol) in THF (2 mL) and
EtOH (0.56 mL) at –70 °C, and Li (52 mg, 7.49 mmol) was added to this solution at the same temperture.
After 30 min, NH4Cl (802 mg, 15.0 mmol) and EtOH (5 mL) were added to the solution and the mixture
was concentrated under the reduced pressure. The resulting residue was extracted with CH2Cl2 (50 mL)
and the organic layer was dried over Na2SO4. The solvent was evaporated in vacuo to give (S)-4-(1-
ethoxy)ethoxy-2-oxopyrrolidine (119 mg, 0.687 mmol, 72%) as an oil. This product (20 mg, 0.115 mmol)
was diluted with 0.1M HCl-MeOH (2 mL) and the solution was stirred for 1 h at room temperture. The
mixture was concentrated under reduced pressure to afford (S)-2 (12.0 mg, 100%) as colorless crystals.
mp 158-159 °C; [α]D25 –57.5° (c 0.780, H2O) (lit.8 [α]D20 –57.8° (c 0.780, H2O)). NMR, mp and HPLC of
this compound were identical with those of (S)-2 obtained from (S)-3.
(S)-4-Hydroxy-2-oxopyrrolidine ((S)-2) from 17
To a solution of 17 (200 mg, 0.938 mmol) in EtOH (5 mL), RhCl3·3H2O (4.9 mg, 0.02 mmol) was added
and the mixture was refluxed for 2 h. After EtOH was removed by evaporation, AcOH (4 mL) and H2O (4
mL) were added to the residue and the mixture was refluxed for 22 h. The mixture was concentrated
under reduced pressure and the residue was washed with CHCl3. The insoluble portion in CHCl3 was
purified by HPLC (column: Nacalai tesque 5C18-AR 250 mm x 20 mm; eluent H2O) to afford (S)-2 (76
25
mg, 80%) as colorless crystals. mp 156-158 °C; [α]D –54.4° (c 0.825, H2O); NMR and HPLC of this
compound were identical with those of (S)-2 obtained from (S)-3.
REFERENCE
1. D. H. Shih, L. Cama, and B. G. Christensen, Tetrahedron Lett., 1985, 26, 587.
2. I. Kawamoto, Drugs Fut., 1998, 23, 181.
3. M. Miyauchi, R. Endo, M. Hisaoka, H. Yasuda, and I. Kawamoto, J. Antibiotics, 1997, 50, 429.
4. M. Miyauchi, O. Kanno, and I. Kawamoto, J. Antibiotics, 1997, 50, 794.
5. S. Banfi, W. Fonio, E. Allievi, M. Pinza, and L. Dorigotti, Farmaco. Ed. Sci., 1984, 39, 16.
6. a) S. Kobayashi, K. Kobayashi, and K. Hirai, Synlett, 1999, 909. b) E. Santaniello, R. Casati, and F.
Milani, J. Chem. Res. (S), 1984, 132.
7. a) M. Kitamura, T. Ohkuma, H. Takaya, and R. Noyori, Tetrahedron Lett., 1988, 29, 1555. b) T.
Suzuki, H. Idogaki, and N. Kasai, Tetrahedron: Asymmetry, 1996, 7, 3109.
8. M. Seki and K. Kondo, Synthesis, 1999, 745.
9. R. Pellegata, M. Pinza, and G. Pifferi, Synthesis, 1978, 614.
10. B. Rajashekhar and E-T. Kaiser, J. Org. Chem., 1985, 50, 5480.