A new approach to (S)-4-hydroxy-2-pyrrolidinone and its 3-substituted analogues

Article abstract of DOI:10.1016/S0957-4166(99)00321-3

Successive treatment of a phenyl thioether derived from (S)-malic acid with n-BuLi, lithium naphthalenide (LN), and electrophiles led to 4-hydroxy- 3-substituted 2-pyrrolidinones in one-pot and in high regio- and diastereoselectivity at C-3. N-Debenzylation of 1-benzyl-4-hydroxy-2- pyrrolidinone using LN afforded naturally occurring (-)-(S)-4-hydroxy-2- pyrrolidinone. (-)-(3S,4S)-4-Hydroxy-3-methyl-2-pyrrolidinone, the lactam form of the γ-amino acid residue found in marine natural products, bistramides, was prepared by the same method.

Full text of DOI:10.1016/S0957-4166(99)00321-3

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3309–3317
A new approach to (S)-4-hydroxy-2-pyrrolidinone and its
3-substituted analogues
Pei Qiang Huang,∗ Xiao Zheng, Shi Li Wang, Jian Liang Ye, Li Ren Jin and Zhong Chen
Department of Chemistry, Xiamen University, Xiamen, Fujian 361005, People’s Republic of China
Received 17 June 1999; accepted 28 July 1999
Abstract
Successive treatment of a phenyl thioether derived from (S)-malic acid with n-BuLi, lithium naphthalenide (LN),
and electrophiles led to 4-hydroxy-3-substituted 2-pyrrolidinones in one-pot and in high regio- and diastereoselec-
tivity at C-3. N-Debenzylation of 1-benzyl-4-hydroxy-2-pyrrolidinone using LN afforded naturally occurring (−)-
(S)-4-hydroxy-2-pyrrolidinone. (−)-(3S,4S)-4-Hydroxy-3-methyl-2-pyrrolidinone, the lactam form of the γ-amino
acid residue found in marine natural products, bistramides, was prepared by the same method. © 1999 Elsevier
Science Ltd. All rights reserved.
The 4-hydroxy-2-pyrrolidinone ring system 1 is present in many biological active compounds (e.g. 2)
and it could act as a versatile intermediate for the syntheses of a wide variety of γ-amino acids (GABA),
substituted 2-pyrrolidinones (e.g. 3 and 4) as well as pyrrolidines. For example, racemic 4-hydroxy-2-
pyrrolidinone 1 has been used in the synthesis of nootropic agent oxiracetam 2;1 (R)-1 has been converted
into two important drugs (R)-γ-amino-β-hydroxybutyric acid (GABOB) 52 and (R)-carnitine (vitamin
BT) 6;2 (S)-1 is a component of Amanita muscaria (L. ex Fr.);3 4-amino-3-hydroxy-2-methylbutyric acid
7 is the γ-amino acid residue found in bistramides A, B, C, D and K, a new class of marine natural
products isolated4 from Lissoclinum bistratum with potent cytotoxic, antiproliferative and neurotoxic
activities. Consequently, the asymmetric synthesis of both enantiomers of 1 has attracted much current
attention.5,6 In continuation of our efforts5d,7 to exploit further cheap and easily available (S)-malic acid
as a useful chiral pool,8 we wish to report herein a new approach to (S)-4-hydroxy-2-pyrrolidinone 1 and
its 3-substituted analogues.
∗
Corresponding author. E-mail: pqhuang@xmu.edu.cn
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00321-3

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Based on the consideration that in a 1-alkyl-2-pyrrolidinone ring system the protons at C-3 are
much more acidic than those at C-5, a one-pot procedure for the synthesis of 2-pyrrolidinones with
general structure 9 from phenyl thioether 8 was envisaged (Scheme 1). This approach implicated
several successive reactions, namely, O-deprotonation, tandem reductive lithiation–proton exchange,
nucleophilic reaction and protonation.
Scheme 1.
1. Results and discussion
The synthesis of the key phenyl thioether 8 started with O-acetyl malimide 10, which was easily
prepared from (S)-malic acid following a one-pot procedure7,8b–d (Scheme 2). Regio- and diastereo-
selective reduction8b–d of 10 with NaBH4 led to cis-118c,d in good yield (90%). In the presence of a
catalytic amount of p-TsOH, the reaction of thiophenol with 11 in dry CH2Cl2 afforded directly the
desired deacetylated thioether 8 in 79% yield and a small amount (11%)9 of thioether 8a. The two
diastereomers trans-8 and cis-8 (in a ratio of 12:1 in favor of trans isomer) are easily separated by
flash chromatography. The stereochemistry of trans-8 and cis-8 was assigned according to the observed
vicinal coupling constants7 (J4,5=6.2 Hz for cis-8 and J4,5=0 Hz for trans-8).
With thioether 8 in hand, we are now in a position to attempt the novel reductive metallation of phenyl
thioether 8. Although the LN or related system mediated reductive lithiation10 is a well documented
procedure, to the best of our knowledge, none of the reported examples deal with the reactions at
position α to the nitrogen of a lactam. We have found that this can be achieved by successive treatment
of trans-8 with n-BuLi, lithium naphthalenide (LN), and an electrophile. Thus treatment of trans-8
with 1.1 molar equivalents of n-BuLi at −78°C, followed by 2.5 molar equivalents of freshly prepared
LN and benzaldehyde led to a pair of separable diastereomers 12a,b (ratio 1:1.2 as determined by
chromatographic separation, combined yield 74%, Table 1, entry 1) and the reduced product 17 (11%
yield). In the same manner, the reaction of transient dianion B with p-anisaldehyde gave 13a,b (1:1.1,
71%), while when using acetone or cyclohexanone as the electrophile, only one diastereomer 14 (41%)
or 15 (40%) was obtained. These results might indicate that the reaction of the transient dianion B with
carbonyl compounds proceeded with high diastereoselectivity at C-3 (in all examples mentioned above,
only one C-3 epimer could be obtained by chromatographic separation in each case), and mediocre

P. Q. Huang et al. / Tetrahedron: Asymmetry 10 (1999) 3309–3317
3311
Scheme 2. Reagents and conditions: (i) Huang et al.,7 Koot et al.,8c and Louwrier et al.,8d 92%. (ii) Koot et al.,8c and Louwrier
et al.,8d 90%. (iii) PhSH, p-TsOH (cat.), CH2Cl2, rt; (iv) n-BuLi; LN, THF, −78°C, electrophiles (see Table 1); (v) LN, THF,
−15 to −10°C
Table 1
Results of the one-pot synthesis of 12–17 from phenyl thioether trans-8
diastereoselectivity at the carbinolic center when using an aldehyde as electrophile. Similarly, the reaction
of the dianion B with methyl iodide produced 16 (49%) and a small amount of an inseparable mixture
consisting of 17 and other unidentified methylated products. Finally, treatment of the dianion B with
methanol gave lactam 17 in a yield of 86.6%.
Based on the observed characteristic geminal coupling constants of the methylene protons at C-3
(e.g. 17 and its C-5 alkylated derivatives,7 Jgem=17.5 Hz) and those at C-5 (e.g. compounds 12–16,
Jgem=ca. 10 Hz), the regiochemistry of the present one-pot reaction was assigned as shown in structures
12–16. The stereochemistry at C-3 of compounds 12–16 was assigned by comparison with those obtained
by alternative methods.11,12 A direct stereochemical proof was gained from a single-crystal X-ray
crystallographic analysis of compound (10S, 4R, 5S)-12b (Fig. 1).
Thus, we have shown that phenyl thioether trans-8 can serve as a synthetic equivalent to chiron B
through a one-pot operation. In this procedure, transient dianion A was converted to the thermodyna-
mically more stable B through proton exchange (Scheme 1). These results open a new approach to

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Figure 1. ORTEP plot of compound 12b (presented as its antipode)
both 3-substituted and 3-unsubstituted 4-hydroxy-2-pyrrolidinones. These 2-pyrrolidinones and their ring
opening products are key intermediates for drugs and agrochemicals.1–6
We next turned our attention to the synthesis of (S)-1. For this purpose, it was needed to cleave
the amidic N-benzyl group in 17. Although several methods are available to effect the amide N-
debenzylation,13,14 the method using dissolved metal in liquid ammonia is the most useful one. Based on
the consideration that solvated electrons are the key species responsible for N-debenzylation in this type
of reaction, it was envisioned that LN would be useful for the same purpose. Thus, treatment of 17 with
6 equivalents of LN led to (S)-1 [mp 156–157°C. [α]22 −53.9 (c 0.5, H2O)] in 40% yield. Similarly, N-
D
debenzylation of 16 using LN afforded 18 [yield 58.7%, mp 135.5–137°C. [α]22 −58.8 (c 0.9, MeOH)],
D
the lactam form of compound syn-7. Since lactam formation is a useful method for confirming the
stereochemistry of the corresponding γ-amino acids,15 present synthesis of lactam syn-7 would provide
a useful reference for the stereochemical assignment of 4-amino-3-hydroxy-2-methylbutyric acid 7, the
γ-amino acid residue (with unknown stereochemistry) found in bistramides A, B, C, D and K.4 It is
also worth mentioning that this amide N-debenzylation method presents the advantage of being easy to
perform and is apparently the first illustration of LN mediated amide N-debenzylation.16
In summary, starting from trans-8, we have developed a concise approach to substituted 2-
pyrrolidinones 12–17. Moreover, we also developed a new LN based amide N-debenzylation method,
which resulted in a new chiral synthesis of naturally occurring (−)-(S)-4-hydroxy-2-pyrrolidinone 1 and
an asymmetric synthesis of 18 as the lactam form of the γ-amino acid residue found in bistramides.
2. Experimental
Melting points were determined on a Yanaco MP-500 micro melting point apparatus. Infrared spectra
were measured with a Nicolet Avatar 360 FT-IR or a Shimadzu IR-408 spectrometer using film NaCl
1
or KBr pellet techniques. H NMR spectra were recorded in CDCl3 or D2O on a Varian unity +500
spectrometer with tetramethylsilane or chloroform as an internal standard. Chemical shifts are expressed
in δ (ppm) units downfield from TMS. Mass spectra were recorded at 70 eV ionizing voltage on one
of the following apparatus: Finnigan Mat-GCQ (direct injection), Hewlett–Packard 5889A or Bruker
APEX II FT mass spectrometer and were presented as m/z (% rel. int.). Optical rotations were measured
with either a Perkin–Elmer 241 MC or a Perkin–Elmer 341 automatic polarimeter. Elemental analyses
were performed by the Micro Analytical Laboratory at either Shanghai Institute of Organic Chemistry or
Department of Chemistry, Xiamen University. THF and diethyl ether used in the reactions were dried by
distillation over metallic sodium and benzophenone; dichloromethane were distilled over P2O5. Silica gel
(Qingdao, 400 mesh) was used for column chromatography, eluting (unless otherwise stated) with ethyl
acetate/petroleum ether (PE) (60–90°C) mixtures. (S)-4-Acetoxy-1-benzyl-2,5-pyrrolidinedione7,8c,8d 10

P. Q. Huang et al. / Tetrahedron: Asymmetry 10 (1999) 3309–3317
3313
and (4S,5S)-4-acetoxy-1-benzyl-5-hydroxy-2-pyrrolidinone 11 were prepared according to the literature
procedures.
2.1. (4S,5R)-1-Benzyl-4-hydroxy-5-thiophenyl-2-pyrrolidinone trans-8 and the 4S,5S-isomer cis-8
To a solution of 11 (523 mg, 2.1 mmol) and p-toluenesulfonic acid monohydrate (50 mg) in 20 mL of
anhydrous CH2Cl2 was added thiophenol (0.43 mL, 4.2 mmol). After stirring at rt for 52 h, a saturated
aqueous solution of NaHCO3 (9 mL) and brine (5 mL) were added. The mixture was extracted with
CH2Cl2 (3×30 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in
vacuo. Flash chromatography (EtOAc:PE 1:1) afforded trans-8 (459 mg, 73%) as a pale yellow oil, cis-
8 (38 mg, 6%) as colorless crystals and a small amount of diastereomeric mixture of undeacetylated
compound 11 (79 mg, 12%).
trans-8 (faster eluting isomer): crystallized on standing at low temperature, mp 76.5–77.5°C. [α]20
D
−60.8 (c 3.0, CHCl3). IR: 3382, 3061, 3032, 2926, 1674, 1583, 1439, 1155, 1252, 1058, 937, 742, 697
1
cm−1. H NMR (500 MHz, CDCl3): 2.08 (ddd, J=1.0, 6.1, 17.6 Hz, 1H, H-3), 2.18 (dd, J=1.1, 17.6
Hz, 1H, H-3), 4.21 (d, J=14.9 Hz, 1H, PhCH2N), 4.48 (s and dd superimposed, J=1.1, 6.1 Hz, 2H, H-5
and H-4), 5.22 (d, J=14.9 Hz, 1H, PhCH2N), 7.25–7.42 (m, 10H, Ph-H). 13C NMR (125 MHz, CDCl3):
39.04 (C-3), 43.70 (NCH2Ph), 71.35 (C-5), 73.62 (C-4), 127.65, 128.07, 128.71, 128.98, 129.39 and
130.29 (Ar-CH), 134.56 (Ar-C), 135.32 (Ar-CS), 173.11 (C_O). MS (EI): 299 (M+, 0.1), 190 (M+−PhS,
57), 172 (5), 109 (7), 92 (9), 91 (100), 65 (17), 51 (3), 39 (5). HRMS calcd for C11H12NO2 (M+−PhS):
190.0868. Found: 190.0868.
cis-8 (slower eluting isomer): mp 76–77°C. [α]20 −18.4 (c 1.9, CHCl3). IR: 3408, 3063, 3032, 2931,
D
1
2902, 1687, 1605, 1583, 1448, 1382, 1235, 1173, 1086, 748, 707 cm−1. H NMR (500 MHz, CDCl3):
2.19 (dd, J=1.3, 16.8 Hz, 1H, H-3), 2.65 (dd, J=7.6, 16.8 Hz, 1H, H-H), 4.15 (d, J=14.8 Hz, 1H, PhCH2N),
4.51 (ddd, J=6.2, 1.3, 7.6 Hz, 1H, H-4), 4.80 (d, J=6.2 Hz, 1H, H-5), 5.24 (d, J=14.8 Hz, 2H, NCH2Ph),
7.18–7.44 (m, 10H, Ph-H). 13C NMR (125 MHz, CDCl3): 38.30 (C-3), 44.35 (PhCH2N), 66.33 (C-5),
75.29 (C-4), 127.79, 128.08, 128.24, 128.54, 128.71, 129.35, 131.68, and 133.69 (Ar-CH), 134.61 (Ar-
C), 135.53 (ArCS), 171.27 (C_O). MS (EI): 299 (M+, 0.1), 190 (M+−PhS, 62), 172 (6), 109 (6), 92 (8),
91 (100), 65 (15), 51 (3), 39 (5). Anal. calcd for C17H17NO2S: C, 68.66; H, 5.68; N, 4.71. Found: C,
68.32; H, 5.70; N, 4.71.
2.2. General procedure for the one-pot synthesis of compounds 12–17 from trans-8
A solution of trans-8 (0.52 mmol) in 1.7 mL of dry THF at −78°C was treated with n-BuLi (1.6 M
solution in n-hexane, 0.57 mmol) and freshly prepared lithium naphthalenide (1.0 M solution in THF,
1.14 mmol). After stirring for 30 min, an electrophile (0.78 mmol) was added. The stirring continued
at −78°C for 1 h, and was then allowed to warm to 0°C. A saturated aqueous solution of NH4Cl was
added and the mixture was extracted with CH2Cl2 (3×5 mL). The combined organic layers were dried
(MgSO4), filtered and concentrated in vacuo. Flash chromatography (EtOAc:PE 1:1) afforded the desired
product and a small amount of 17 (Table 1).
2.3. (10R,3R,4S)-1-Benzyl-4-hydroxy-3-[(10 -phenyl)-hydroxymethyl]-2-pyrrolidinone 12a and the (10S,
3R,4S)-isomer 12b
12a (faster eluting isomer): yield 33.8%, white crystals, mp 92–93°C. [α]20 +44.6 (c 1.3, CHCl3). IR:
D
3350, 2900, 1660, 1480, 1445, 1270, 1040, 695 cm−1. 1H NMR (500 MHz, CDCl3): 2.10 (s, br, 1H, OH),

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P. Q. Huang et al. / Tetrahedron: Asymmetry 10 (1999) 3309–3317
2.85 (dd, J=2.4, 4.7 Hz, 1H, H-3), 2.99 (dd, J=4.8, 10.1 Hz, 1H, H-5), 3.32 (dd, J=7.4, 10.1 Hz, 1H, H-5),
4.41 (d, J=15.0 Hz, 1H, PhCH2N), 4.44 (d, J=15.0 Hz, 1H, PhCH2N), 4.47 (ddd, J=4.7, 4.8, 7.4 Hz, 1H,
H-4), 5.35 (d, J=2.4 Hz, 1H, CH(OH)Ph), 7.18–7.34 (m, 10H, Ph-H). 13C NMR (75 MHz, CDCl3): 46.36
(C-5), 53.11 (C-3), 58.45 (NCH2Ph), 65.28 (C-4), 70.80 (PhCHOH), 125.55, 127.64, 127.92, 128.57 and
128.65 (Ar-CH), 135.58 and 141.43 (2×Ar-C), 172.97 (C_O). MS (EI): 297 (M+, 19), 279 (M+−H2O,
10), 190 (28), 174 (34), 131 (10), 106 (11), 91 (100), 77 (12). HRMS calcd for C18H19NO3: 297.1365.
Found: 297.1363. Anal. calcd for C18H19NO3: C, 72.73; H, 6.40; N, 4.71. Found: C, 72.86; H, 6.41; N,
4.69.
12b (slower eluting isomer): yield 40.5%, crystallized on standing at low temperature as white crystals,
mp 113–114°C. [α]20 −9.7 (c 1.0, CHCl3). IR: 3500, 2800, 1660, 1480, 1450, 1270, 1040, 695 cm−1. 1H
D
NMR (500 MHz, CDCl3): 2.76 (dd, J=7.1, 9.2 Hz, 1H, H-3), 3.03 (dd, J=6.4, 10.1 Hz, 1H, H-5), 3.30 (dd,
J=7.6, 10.1 Hz, 1H, H-5), 4.18 (ddd, J=6.4, 7.1, 7.6 Hz, 1H, H-4), 4.43 (d, J=14.7 Hz, 1H, PhCH2N), 4.48
(d, J=14.7 Hz, 1H, PhCH2N), 4.85 (d, J=9.2 Hz, 1H, CH(OH)Ph), 7.18–7.34 (m, 10H, Ph-H). 13C NMR
(75 MHz, CDCl3): 46.24 (C-5), 51.89 (C-3), 56.89 (NCHPh), 66.99 (C-4), 74.68 (PhCHOH), 126.68,
127.89, 128.15, 128.66, 128.84 and 128.99 (Ar-CH), 135.41 and 140.33 (2×Ar-C), 173.58 (C_O). MS
(EI): 297 (M+, 19), 279 (M+−H2O, 10), 190 (28), 174 (34), 131 (10), 106 (11), 91 (100), 77 (12). HRMS
calcd for C18H19NO3: 297.1365. Found: 297.1363.
2.4. (10R,3R,4S)-1-Benzyl-4-hydroxy-3-[10 -(4-methoxyphenyl)-hydroxymethyl]-2-pyrrolidinone 13a
and the (10S,3R,4S)-isomer 13b
13a (faster eluting isomer): yield 33.3%, pale yellow solid, mp 117–119°C. [α]20 +32.5 (c 1.0,
D
CHCl3). IR: 3400, 2950, 1660, 1510, 1440, 1250, 1170, 1025, 800 cm−1. 1H NMR (500 MHz, CDCl3):
2.85 (dd, J=3.9, 5.8 Hz, 1H, H-3), 3.02 (dd, J=5.5, 10.1 Hz, 1H, H-5), 3.34 (dd, J=7.6, 10.1 Hz, 1H, H-5),
3.80 (s, 3H, OCH3), 4.47 (s, 2H, PhCH2N), 4.53 (ddd, J=5.5, 5.8, 7.6 Hz, 1H, H-4), 5.37 (d, J=3.9 Hz,
1H, ArCHOH), 6.90 (d, J=8.3 Hz, 2H, CH3OC6H4), 7.20 (d, J=8.3 Hz, 2H, CH3OC6H4), 7.29–7.34 (m,
5H, Ph-H). 13C NMR (125 MHz, CDCl3): 46.37 (C-5), 52.72 (C-3), 55.30 (NCH2Ph), 58.32 (CH3O),
65.68 (C-4), 70.77 (PhCHOH), 114.16, 126.72, 127.68, 128.03 and 128.75 (Ar-CH), 133.24 and 135.73
(2×Ar-C), 159.12 (Ar-COMe). MS (EI): 327 (M+, 20), 191 (100), 174 (47) 91 (10). HRFABMS calcd
for [C19H21O4N+H]+ 328.1543. Found: 328.1542.
13b (slower eluting isomer): yield 37.4%, pale yellow solid, mp 123–125°C. [α]20 −14.4 (c 1.2,
D
CHCl3). IR: 3400, 2950, 1660, 1510, 1440, 1250, 1170, 1025, 800 cm−1. 1H NMR (500 MHz, CDCl3):
2.74 (dd, J=7.0, 9.2 Hz, 1H, H-3), 3.02 (dd, J=6.3, 10.1 Hz, 1H, H-5), 3.28 (dd, J=8.0, 10.1 Hz, 1H, H-5),
3.80 (s, 3H, OCH3), 4.14 (ddd, J=6.3, 7.0, 8.0 Hz, 1H, H-4), 4.42 (d, J=14.7 Hz, 1H, PhCH2N), 4.46 (d,
J=14.7 Hz, 1H, PhCH2N), 4.79 (d, J=9.2 Hz, 1H, ArCHOH), 6.90 (d, J=8.3 Hz, 2H, CH3OC6H4), 7.18
(d, J=8.3 Hz, 2H, CH3OC6H4), 7.27–7.35 (m, 5H, Ph-H). 13C NMR (125 MHz, CDCl3): 46.22 (C-5),
51.92 (C-3), 55.27 (NCH2Ph), 56.93 (CH3O), 67.02 (C-4), 74.20 (PhCHOH), 114.28, 127.87, 127.94,
128.15 and 128.82 (Ar-CH), 132.28 and 135.42 (2×Ar-C), 159.68 (Ar-COMe), 173.68 (C_O). MS (EI):
327 (M+, 11), 191 (100), 174 (47), 91 (12). HRFABMS calcd for [C19H21O4N+H]+: 328.1543. Found:
328.1545.
2.5. (3R,4S)-1-Benzyl-4-hydroxy-3-[(10 -hydroxy-10-methyl)ethyl]-2-pyrrolidinone 14
Yield 40.8%, pale yellow oil, [α]20 −25.4 (c 2.3, CHCl3). IR: 3350, 2900, 1655, 1445, 1255, 695
D
cm−1. 1H NMR (500 MHz, CDCl3): 1.29 (s, 3H, CH3), 1.35 (s, 3H, CH3), 2.57 (d, J=6.5 Hz, 1H, H-3),
3.08 (dd, J=5.6, 10.1 Hz, 1H, H-5), 3.45 (dd, J=7.6, 10.1 Hz, 1H, H-5), 4.32 (ddd, J=5.6, 6.5, 7.6 Hz, 1H,

P. Q. Huang et al. / Tetrahedron: Asymmetry 10 (1999) 3309–3317
3315
H-4), 4.41 (d, J=14.9 Hz, 1H, PhCH2N), 4.52 (d, J=14.9 Hz, 1H, PhCH2N), 7.20–7.38 (m, 5H, Ph-H).
13C NMR (125 MHz, CDCl3): 26.50 (CH3), 27.19 (CH3), 46.22 (C-5), 53.05 (C-3), 60.10 (NCH2Ph),
67.33 (C-4), 71.50 (Me2COH), 127.78, 128.02 and 128.77 (Ar-CH), 135.54 (Ar-C), 173.52 (C_O). MS
(EI): 249 (M+, 13), 231 (M+−H2O, 8), 191 (26), 174 (22), 173 (25), 111 (11), 97 (17), 91 (100), 57 (64).
HRMS calcd for C14H19NO3: 249.1365. Found 249.1366.
2.6. (3R,4S)-1-Benzyl-4-hydroxy-3-(10 -hydroxycyclohex-10 -yl)-2-pyrrolidinone 15
Yield 40%, pale yellow oil, [α]20 −24.7 (c 2.1, CHCl3). IR: 3350, 2940, 1655, 1490, 1260, 1075, 960,
D
690 cm−1. 1H NMR (500 MHz, CDCl3): 1.18–1.82 (m, 10H, (CH2)5), 2.53 (d, J=6.1 Hz, 1H, H-3), 3.07
(dd, J=5.5, 10.2 Hz, 1H, H-5), 3.44 (dd, J=7.7, 10.2 Hz, 1H, H-5), 4.43 (ddd, J=5.5, 6.1, 7.7 Hz, 1H,
H-4), 4.46 (d, J=14.7 Hz, 1H, PhCH2N), 4.51 (d, J=14.7 Hz, 1H, PhCH2N), 7.20–7.37 (m, 5H, Ph-H).
13C NMR (125 MHz, CDCl3): 21.05, 21.23, 25.50, 33.72 and 34.88 (c-hex-CH2), 46.16 (C-5), 52.96
(C-3), 60.34 (NCH2Ph), 66.83 (C-4), 72.32 (c-hex-COH), 127.71, 128.00, and 128.74 (Ar-CH), 135.64
(Ar-C), 173.26 (C_O). MS (EI): 289 (M+, 6), 271 (M+−H2O, 58), 191 (13), 174 (40.6), 111 (11), 97
(17), 91 (100), 71 (38), 57 (60). HRMS calcd for C17H23NO3: 289.1678. Found 289.1676.
2.7. (3S,4S)-1-Benzyl-4-hydroxy-3-methyl-2-pyrrolidinone 16
Yield 48.5%, pale yellow oil, [α]20 −47.3 (c 0.8, CHCl3). IR: 3350, 2850, 1660, 1485, 1450, 1260,
D
1
1075, 695 cm−1. H NMR (500 MHz, CDCl3): 1.23 (d, J=7.3 Hz, 3H, CH3), 2.44 (dq, J=5.5, 7.3 Hz,
1H, H-3), 3.08 (dd, J=4.6, 10.3 Hz, 1H, H-5), 3.42 (dd, J=6.5, 10.3 Hz, 1H, H-5), 4.03 (ddd, J=4.6, 5.5,
6.5 Hz, 1H, H-4), 4.41 (d, J=14.8 Hz, 1H, PhCH2N), 4.46 (d, J=14.8 Hz, 1H, PhCH2N), 7.19–7.33 (m,
5H, Ph-H). 13C NMR (75 MHz, CDCl3): 13.66 (CH3), 46.19 (C-5), 52.86 (C-3), 60.09 (NCH2Ph), 72.19
(C-4), 127.59, 127.96 and 128.69 (Ar-CH), 136.07 (Ar-C), 175.34 (C_O). MS (EI): 205 (M+, 100), 172
(8), 160 (12), 132 (13), 119 (14), 107 (12), 91 (28). HRFABMS calcd for [C12H15NO2+H]+: 206.1175.
Found: 206.1177.
2.8. (S)-1-Benzyl-4-hydroxy-2-pyrrolidinone 17
Yield 86.6%, white solid, mp 107.5–109°C, [α]20 −35.2 (c 1.3, CHCl3). IR: 3350, 2910, 1660, 1485,
D
1440, 1260, 1078, 690 cm−1. 1H NMR (500 MHz, CDCl3): 2.44 (dd, J=2.3, 17.4 Hz, 1H, H-3), 2.70 (dd,
J=6.6, 17.4 Hz, 3H, H-3), 3.18 (dd, J=2.0, 10.9 Hz, 1H, H-5), 3.48 (dd, J=5.6, 10.9 Hz, 1H, H-5), 4.42
(d, J=14.9 Hz, 1H, PhCH2N), 4.45 (m, 1H, H-4), 4.48 (d, J=14.9 Hz, 1H, PhCH2N), 7.18–7.38 (m, 5H,
Ph-H). 13C NMR (75 MHz, CDCl3): 41.08 (C-3), 46.28 (C-5), 55.76 (NCH2Ph), 63.96 (C-4), 127.58,
127.91, and 128.67 (Ar-CH), 135.85 (Ar-C), 173.22 (C_O). MS (EI): 191 (M+, 100), 172 (28), 146 (36),
118 (19), 104 (22), 91 (48), 65 (11). HRMS calcd for C11H13NO2: 191.0946. Found: 191.0946. Anal.
calcd for C11H13NO2: C, 69.11; H, 6.81; N, 7.33. Found: C, 69.01; H, 6.86; N, 7.27.
2.9. (S)-4-Hydroxy-2-pyrrolidinone 1
A solution of 17 (45 mg, 0.236 mmol) in 2.3 mL of dry THF at −20°C was treated with n-BuLi (1.6 M
solution in n-hexane, 0.22 mL, 0.35 mmol) and freshly prepared lithium naphthalenide (1.5 M solution
in THF, 0.94 mL, 1.41 mmol). After stirring at −15 to −10°C for 75 min, the reaction was quenched by
MeOH and concentrated in vacuo. Flash chromatography (CHCl3:MeOH 4:1) afforded 1 (9 mg, 38.7%)
as a white solid. Mp 156–157°C (lit. for (S)-1: 153.5–155°C;3 155–157°C;5a 152–154°C;5d for (R)-1:

3316
P. Q. Huang et al. / Tetrahedron: Asymmetry 10 (1999) 3309–3317
157–158°C;5a 153–155°C;2). [α]20 −53.9 (c 0.6, H2O) [lit. for (S)-1: [α]D −45.8 (H2O);3 [α]25 −55.5
D
D
(c 1.04, H2O);5a [α]D −54.8 (c 0.48, H2O)];5d [α]21 −34.5 (c 1.4, H2O)], 60% ee;5b for (R)-1, [α]D
D
+57.3 (c, 1.4, H2O);5a [α]D +58.6 (c 0.36, H2O).2 IR: 3246, 3147, 2943, 2929, 1674, 1483, 1408, 1338,
1
1304, 1065, 968, 744, 685 cm−1. H NMR (500 MHz, D2O): 2.20 (dd, J=1.7, 17.8 Hz, 1H, H-3), 2.72
(dd, J=6.3, 17.8 Hz, 1H, H-3), 3.29 (dd, J=11.8 Hz, 1H, H-5), 3.65 (dd, J=5.3, 11.8 Hz, 1H, H-5), 4.55
(m, 1H, H-4). 13C NMR (75 MHz, D2O): 39.56 (C-3), 51.41 (C-5), 66.80 (C-4), 179.36 (C_O). MS (EI):
102 (M++1, 32), 91 (52), 84 (18), 73 (100), 65 (9). HRFABMS calcd for [C4H7NO2 +H]+: 102.0549.
Found: 102.0550.
2.10. (3S,4S)-4-Hydroxy-3-methyl-2-pyrrolidinone 18
A solution of 16 (85 mg, 0.41 mmol) in 4.1 mL of dry THF at −20°C was treated with n-BuLi (1.6 M
solution in n-hexane, 0.29 mL, 0.46 mmol) and freshly prepared lithium naphthalenide (1.5 M solution in
THF, 1.66 mL, 2.49 mmol). After stirring at −15 to −10°C for 2 h, the reaction was quenched by MeOH
and concentrated in vacuo. Flash chromatography (CHCl3:MeOH 8:1) afforded 18 (28 mg, 58.7%) as
a white solid and recovered starting material 16 (20 mg, 24%). 18: mp 135.5–136.5°C. [α]20 −58.8 (c
0.9, MeOH). IR: 3232, 3145, 2970, 2929, 1671, 1486, 1461, 1329, 1295, 1122, 976, 832 cm−1D. 1H NMR
(500 MHz, D2O): 1.15 (d, J=7.6 Hz, 3H, CH3), 2.38 (dq, J=4.6, 7.6 Hz, 1H, H-3), 3.20 (dd, J=4.1, 11.1
Hz, 1H, H-5), 3.66 (dd, J=6.2, 11.1 Hz, 1H, H-5), 4.18 (ddd, J=4.1, 4.6, 6.2 Hz, 1H, H-4). 13C NMR (75
MHz, D2O): 12.56 (CH3), 45.19 (C-3), 46.56 (C-5), 73.57 (C-4), 181.65 (C_O). MS (EI): 115 (M+, 17),
100 (24), 86 (100), 82 (19), 57 (38). HRFABMS calcd for [C5H9NO2+H]+: 116.0706. Found: 116.0706.
Anal. calcd for C5H9NO2: C, 52.17; H, 7.83; N, 12.17. Found: C, 51.90; H, 7.93; N, 12.11.
Acknowledgements
This work is supported by the National Science Fund for Distinguished Young Investigator (no.
29625204). The National NSF of China (no. 29572065) is thanked for additional support.
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