A new approach for the asymmetric synthesis of (2S,3S)-3-hydroxypipecolic acid

Article abstract of DOI:10.1016/j.tetasy.2008.04.031

An efficient stereoselective synthesis of (2S,3S)-3-hydroxypipecolic acid was achieved from (S)-glutamic acid via the furylation of an N-protected 6-hydroxy-2-piperidinone using furan as a nucleophile and the oxidation of the furyl group to a carboxylic group as the key steps.

Full text of DOI:10.1016/j.tetasy.2008.04.031

Tetrahedron: Asymmetry 19 (2008) 1200–1203
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A new approach for the asymmetric synthesis of (2S,3S)-3-hydroxypipecolic acid
a
a,
Liang-Xian Liu a,b, , Qi-Long Peng , Pei-Qiang Huang
*
*
a Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen,
Fujian 361005, PR China
b Department of Chemistry and Biology, Ganan Teachers’ College, Ganzhou, Jiangxi 341000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient stereoselective synthesis of (2S,3S)-3-hydroxypipecolic acid was achieved from (S)-glutamic
acid via the furylation of an N-protected 6-hydroxy-2-piperidinone using furan as a nucleophile and the
oxidation of the furyl group to a carboxylic group as the key steps.
Received 6 March 2008
Accepted 24 April 2008
Available online 26 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
OH
OH
O
OH
OH
N
Me
H
H
Chiral hydroxylated piperidines are important core structures
that can be found in many bioactive natural and non-natural com-
pounds. These compounds have received considerable attention on
account of their many pharmacological properties.1 3-Hydroxy-
pipecolic acid is an interesting natural compound since it may be
seen as a conformationally constrained serine derivative, or a
hydroxylated homoproline,2 and has shown inhibitory activity
against b-N-acetylglucosaminidase as well as Escherichia coli b-glu-
curonidase.3 Moreover, this 3-hydroxypiperidine unit is found in a
number of biologically important products. For example, the cis-
isomer 1 forms a part of the structure of tetrazomine 3,4 an antitu-
mor antibiotic, while the trans-isomer 2 is a precursor of (ꢀ)-
N
N
H
N
CO2H
H
N
CO2H
NH
OMe
O
H
1
H
2
3
OH
HO
OH
O
OH
OH
OH
OH
O
H
N
N
H
OH
O
N
N
4
N
H
6
OBn
5
OH
OBn
OBn
OBn
CN
O
N
P
(S)-7
O
N
O
O
N
OH
HO
N
O
O
N
P
(S)-8
Bn
Bn
Bn
swainsonine 4, which has shown potent and specific a-D-mannos-
(5S,6RS)-9a
idase inhibitory activity,5 and can be found in the structure of
febrifugine 5, a potent antimalarial agent. In addition, 3-hydrox-
ypiperidine unit also is found in polyhydroxylated nitrogen hetero-
cycles (azasugars) representing sugar analogues. Many of these
azasugars, which are frequently inhibitors of carbohydrate-pro-
cessing enzymes, have the potential for use in a wide range of
potential therapeutic strategies including the treatment of viral
infections, cancer, diabetes, tuberculosis, and lysosomal storage
diseases, as well as being inhibitors of the growth of parasitic pro-
tozoa (Fig. 1).6
Recently, we have shown that protected (S)-3-hydroxyglutari-
mides 7 and 8 (P = PMB, Bn) were versatile building blocks for
the asymmetric synthesis of 3-hydroxy and 3-amino-piperidines.7
Starting from 7 and 8, different methods have been developed for
establishing (2S,3S)-, (2R,3R)- or (2R,3S)-stereochemistry of 2-
substituted 3-hydroxypiperidines.8
(3S,6RS)-9b
10
(a. P=PMB; b. P=Bn)
Figure 1.
pounds, as a part of our research program aimed at developing
enantioselective syntheses of naturally occurring bioactive com-
pounds, we decided to explore the introduction of the carboxyl
group at the C-2 of 8 and we became interested in developing a
simple and feasible route to 3-hydroxypipecolic acid.9 Herein, we
report an enantioselective synthesis of 2 employing the furylation
and oxidation of a furyl group to a carboxylic group as the key
steps.
2. Results and discussion
In continuation of our interest in the amino acid chiral tem-
plate-assisted synthesis of natural and non-natural bioactive com-
The requisite (S)-3-benzyloxyglutarimide 8 (P = Bn) was pre-
pared essentially by the known procedure from inexpensive com-
mercially available (S)-glutamic acid in 57% yield (three steps).8a
Controlled reduction of (S)-8 with sodium borohydride (MeOH,
CH2Cl2, 0.5 h, ꢀ15 °C) led to the formation of both C-2 and C-6
* Corresponding authors.
E-mail address: lxliu@xmu.edu.cn (L.-X. Liu).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.04.031

L.-X. Liu et al. / Tetrahedron: Asymmetry 19 (2008) 1200–1203
1201
partially reduced products 9a and 9b in a 95:5 ratio with a com-
3. Conclusion
bined yield of 90% (Scheme 1).
In conclusion, we have described a concise and straightforward
asymmetric synthesis of (2S,3S)-3-hydroxypipecolic acid 2 using a
versatile chiral building block (S)-3-hydroxyglutarimide 8. The
overall yield of 2 from (S)-glutamic acid was 13.3%. Piperidinone
11 should be useful as a chiral building block for the synthesis of
piperidine-related alkaloids, especially polyhydroxylated nitrogen
heterocycles (azasugars) representing sugar analogues.
OBn
OBn
OH
OBn
O
NaBH4, -15 o
C
+
O
N
Bn
(S)-8
O
O
N
HO
N
MeOH/CH2Cl2
90%
Bn
Bn
(5S,6RS)-9a
(3S,6RS)-9b
OBn
OBn
RuCl3/NaIO4, 0 o
C
BF3 OEt2, Furan
9a
O
O
N
CO2H
THF, 0 o
71%
C
O
N
CH3CN/AcOEt/H2O
70%
4. Experimental
4.1. General
Bn
Bn
12
11
OBn
CO2CH3
OBn
BH3 SMe2, 5 o
68%
C
SOCl2, MeOH, rt
86%
Melting points were determined on a Yanaco MP-500 micro
melting point apparatus and are uncorrected. Infrared spectra were
measured with a Nicolet Avatar 360 FT-IR spectrometer using film
KBr pellet techniques. 1H NMR spectra were recorded in CDCl3 on a
Bruker 400 spectrometer with tetramethylsilane as an internal
standard. Chemical shifts are expressed in d (ppm) units downfield
from TMS. Mass spectra were recorded by a Bruker Dalton ESquire
3000 plus liquid chromatography–mass spectrum (direct injec-
tion). Optical rotations were measured with Perkin–Elmer 341
automatic polarimeter. Flash column chromatography was carried
out with silica gel (300–400 mesh). THF was distilled over sodium
benzophenone ketyl under N2.
N
O
N
CO2CH3
Bn
14
Bn
13
OH
1) LiOH, THF/H2O,
70 oC
N
H
CO2H
2) Pd(OH)2/C, EtOH
51%
2
Scheme 1.
With 9a in hand, two routes to the 6-carboxyl-2-piperidinone
were possible. Considering the corresponding amide could be
obtained when 10 being hydrolyzed,10 the oxidation of the furyl
group to a carboxyl group with RuCl3/NaIO4 was initially tried. Ini-
tially, we introduced the furyl group in 11. Treatment of 9a with
furan and borontrifluoride etherate in THF at rt for 12 h led to
the 11 in 65% yield, but the diastereoselectivity was low [(5S,6S)-
11/(5S,6R)-11 diastereoselective ratio: ꢁ1:1]. After several unsuc-
cessful attempts, including using Me3SiCl as a Lewis acid, we were
delighted to find that the reaction at lower temperature provided a
better result. Compound 9a was treated with furan and borontri-
fluoride etherate in THF at 0 °C for 24 h, the desired product 11
was obtained in 71% yield as a 80:20 mixture of diastereomers
(determined by 1H NMR analysis). The stereochemistry of the ma-
jor diastereomer 11 was assigned as trans-11, according to the ob-
served small vicinal coupling constants (J5,6 = 1.0 Hz),8 which was
further confirmed by converting 11 to the known compound 2.
Since the major stereomer (5S,6S)- and minor (5S,6R)-piperidinone
11 which could only be separated partly by column chromatogra-
phy while the cis-ester 14 could only be inverted partly to the cor-
responding diastereomer trans-ester 14 under basic conditions, the
diastereomeric mixture was used directly without further separa-
tion in the next step. Oxidation of 11 with RuCl3/NaIO4 in a mixture
of CH3CN/EtOAc/H2O in a ratio of 4.5/4.5/2 at 0 °C for 5 min affor-
ded 12 in 70% yield. Its vicinal coupling constants (J5,6 = 1.2 Hz) is
consistent with (5S,6S)-11 (J5,6 = 1.0 Hz).
4.2. (5S,6RS)-1-Benzyl-5-benzyloxy-6-hydroxy-2-piperidinone
9a
To a cooled solution of 8 (1.28 g, 4.14 mmol) in MeOH/CH2Cl2
(3:1, 40 mL) was added NaBH4 (0.47 g, 12.37 mmol). After being
stirred for 30 min, the reaction mixture was quenched by the suc-
cessive addition of saturated aqueous NaHCO3 (15 mL) and brine
(20 mL). The aqueous phase was extracted with CH2Cl2
(3ꢃ20 mL). The combined organic extracts were washed with brine
(5 mL), dried over anhydrous Na2SO4, filtered, and concentrated.
The residue was purified by flash chromatography (eluent:
EtOAc/PE = 1:2) to give 1.11 g of cis-9a and trans-9a (combined
yield 86%). Major diastereoisomer: White solid. Mp 135–137 °C
20
(EtOAc/PE = 1:1). ½aꢂD ¼ ꢀ29:8 ðc 1:0; CHCl3Þ. IR (film) mmax: 3183,
2864, 1604, 1478, 1454 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.78
.
(dddd, J = 15.6, 6.6, 5.8, 3.3 Hz, 1H, H-4), 2.16 (dddd, J = 15.6, 9.7,
9.0, 5.8 Hz, 1H, H-4), 2.36 (ddd, J = 17.8, 9.0, 6.6 Hz, 1H, H-3),
2.60 (ddd, J = 17.8, 5.8, 5.8 Hz, 1H, H-3), 3.61 (ddd, J = 9.4, 3.4,
3.3 Hz, 1H, H-5), 3.96 (d, J = 6.0 Hz, 1H, OH), 4.18 (d, J = 14.8 Hz,
1H, NCH2), 4.46 (d, J = 11.7 Hz, 1H, OCH2), 4.55 (d, J = 11.7 Hz, 1H,
OCH2), 4.81 (dd, J = 6.0, 3.4 Hz, 1H, H-6), 5.20 (d, J = 14.8 Hz, 1H,
NCH2), 7.13–7.35 (m, 10H, Ph–H). 13C NMR (100 MHz, CDCl3): d
20.59 (C-4), 28.65 (C-3), 46.42 (NCH2), 70.76, 73.53, 78.07 (C-6),
127.08, 127.57 (2C), 127.86, 127.95 (2C), 128.34 (2C), 128.35
(2C), 137.10, 137.25, 169.68 (C@O). MS (ESI): 312 (M++1, 10), 334
(M++23, 100). Anal. Calcd for C19H21NO3: C, 73.29; H, 6.80; N,
With the 2-piperidinone-6-carboxylic acid 12 in hand, the
esteration of 12 with SOCl2/MeOH proceeded easily to afford ester
13 in 86% yield. Use of the borane dimethyl sulfide complex as
reductant led to piperidine-2-carboxylic acid methyl ester 14 in
68% yield.
Methyl ester 14 was hydrolyzed under basic conditions (LiOH,
THF, H2O, 70 °C, 3 h) to afford the corresponding acid. It is fortu-
nate that the minor protected (5S,6R)-piperidine-2-carboxylic acid
or its ester could be inverted partly to corresponding diastereomer
(5S,6S)-piperidine-2-carboxylic acid or its ester under basic condi-
4.50. Found: C, 73.16; H, 6.52; N, 4.09. Regioisomer 9b (57 mg,
20
4%): White crystal. Mp 67–70 °C (EtOAc/PE = 1:1). ½aꢂD
¼
ꢀ83:5 ðc 1:1; CHCl3Þ. IR (film) mmax
: 3316, 2930, 1620, 1496,
1454 cmꢀ1 1H NMR (400 MHz, CDCl3): d 1.85–1.95 (m, 1H, H-5),
.
2.15–2.36 (m, 1H, H-5), 2.33 (ddd, J = 17.9, 4.5, 1.7 Hz, 1H, H-4),
2.62 (ddd, J = 17.9, 6.8, 5.1 Hz, 1H, H-4), 3.65 (dd, J = 4.3, 2.2 Hz,
1H, H-3), 4.13 (d, J = 15.4 Hz, 1H, NCH2), 4.31 (d, J = 11.7 Hz, 1H,
OCH2), 4.41 (d, J = 11.7 Hz, 1H, OCH2), 4.80–4.88 (m, 1H, H-6),
5.18 (d, J = 15.4 Hz, 1H, NCH2), 5.26 (s, 1H, OH), 7.13–7.35 (m,
10H, Ph–H). 13C NMR (100 MHz, CDCl3): d 20.21, 27.27, 46.78
(NCH2), 70.52, 74.22, 79.72 (C-6), 127.08, 127.52 (2C), 127.97
(2C), 128.23 (2C), 128.38 (2C), 128.56 (2C), 128.69, 137.03,
tions. Finally, deprotection afforded the desired (2S,3S)-3-hydroxy-
25
pipecolic acid 2 {mp 228–235 °C; lit.11 mp 230–238 °C. ½aꢂD
¼
20
þ13:3 ðc 0:7; 10% aq HClÞ; lit.11 ½aꢂD ¼ þ12:9 ðc 0:23; 10% aq HClÞ}
in 51% yield (two steps).

1202
L.-X. Liu et al. / Tetrahedron: Asymmetry 19 (2008) 1200–1203
137.82, 170.80 (C@O). MS (ESI): 312 (M++1, 5), 334 (M++23, 100).
Anal. Calcd for C19H21NO3: C, 73.29; H, 6.80; N, 4.50. Found: C,
72.96; H, 6.84; N, 4.43.
H2O (5 mL). The mixture was extracted with CH2Cl2 (3 ꢃ 10 mL),
and the combined organic extracts were washed with brine and
dried over Na2SO4. Solvent was removed under vacuum, and the
residue was purified by flash column chromatography (EtOAc/hex-
4.3. (5S,6S)-1-Benzyl-5-benzyloxy-6-(2-furyl)-2-piperidinone
11
ane = 1:1) to yield 13 (269 mg, 86%) as
a
colorless oil.
2982, 1732, 1641,
1H NMR (400 MHz, CDCl3): d 1.88 (ddd, J = 16.4,
20
½aꢂD ¼ ꢀ52:9 ðc 2:1; CHCl3Þ. IR (neat) mmax
:
1496, 1064 cmꢀ1
.
To a stirred solution of 9a (190 mg, 0.61 mmol) and furan
(0.22 mL, 3.05 mmol) in anhydrous THF (5 mL) at 0 °C under a
nitrogen atmosphere was added borontrifluoride etherate
(0.23 mL, 1.85 mmol) dropwise. After being stirred for 24 h at that
temperature, the reaction mixture was quenched by the addition of
saturated aqueous NH4Cl solution (5 mL) and H2O (5 mL). The mix-
ture was extracted with CH2Cl2 (3 ꢃ 10 mL), and the combined or-
ganic extracts were washed with brine and dried over Na2SO4.
Solvent was removed under vacuum, and the residue was purified
by flash column chromatography (EtOAc/hexane = 1:6) to yield 11
4.9, 2.0 Hz, H-4), 2.04 (ddd, J = 16.4, 7.0, 2.0 Hz, H-4), 2.50 (ddd,
J = 18.0, 6.9, 2.0 Hz, H-3), 2.75 (ddd, J = 18.0, 7.0, 4.9 Hz, H-3),
3.72 (s, 3H, OCH3), 3.74 (d, J = 15.2 Hz, 1H, NCH2), 4.01 (dt, J = 4.4,
2.1 Hz, 1H, H-5), 4.24 (t, J = 2.1 Hz, 1H, H-6), 4.32 (d, J = 11.7 Hz,
1H, OCH2), 4.37 (d, J = 11.7 Hz, 1H, OCH2), 5.55 (d, J = 15.2 Hz, 1H,
NCH2), 7.18–7.40 (m, 10H, Ph–H). 13C NMR (100 MHz, CDCl3): d
23.61, 27.06, 48.84 (NCH2), 52.71 (OCH3), 61.72 (OCH2), 70.35,
72.10, 127.30 (2C), 127.45, 127.75, 128.15 (2C), 128.36 (2C),
128.54 (2C), 136.26, 137.34, 169.72 (C@O), 170.56 (C@O). MS
(ESI): 354 (M++1, 100). Anal. Calcd for C21H23NO4: C, 71.37; H,
6.56; N, 3.96. Found: C, 70.89; H, 6.57; N, 3.78.
25
(156 mg, 71%) as a colorless oil. ½aꢂD ¼ ꢀ54:9 ðc 0:8; CHCl3Þ. IR
(neat) mmax
: .
3030, 2929, 1656, 1453, 1070 cmꢀ1 1H NMR
(400 MHz, CDCl3): d 1.96 (dddd, J = 18.3, 7.2, 4.5, 2.5 Hz, 1H, H-4),
2.05 (dddd, J = 18.3, 8.9, 6.8, 2.1 Hz, 1H, H-4), 2.53 (ddd, J = 17.9,
8.9, 2.5 Hz, 1H, H-3), 2.79 (ddd, J = 17.9, 7.2, 6.8 Hz, 1H, H-3),
3.58 (d, J = 15.3 Hz, 1H, NCH2), 3.86 (ddd, J = 4.5, 2.1, 1.0 Hz, 1H,
H-5), 4.36 (d, J = 11.7 Hz, 1H, OCH2), 4.42 (d, J = 11.7 Hz, 1H,
OCH2), 4.64 (d, J = 1.0 Hz, 1H, H-6), 5.62 (d, J = 15.3 Hz, 1H,
NCH2), 6.21 (d, J = 3.2Hz, 1H), 6.36 (dd, J = 3.2, 1.9 Hz, 1H), 7.16–
7.34 (m, 10H, Ph–H), 7.36 (d, J = 1.9Hz, 1H). 13C NMR (100 MHz,
CDCl3): d 22.26, 27.32, 47.59 (NCH2), 57.59 (OCH2), 70.42, 73.81,
108.18, 110.51, 127.26 (2C), 127.32, 127.67, 127.87 (2C), 128.37
(2C), 128.54 (2C), 136.83, 137.77, 142.66, 151.88, 169.96 (C@O).
MS (ESI): 362 (M++1, 100). Anal. Calcd for C23H23NO3: C, 76.43;
H, 6.41; N, 3.88. Found: C, 76.86; H, 6.71; N, 4.01.
4.6. (2S,3S)-1-Benzyl-3-benzyloxypiperidine-2-carboxylic acid
methyl ester 14
To an ice-cold solution of 13 (125 mg, 0.35 mmol) in dry THF
(4 mL) was added borane dimethyl sulfide complex (0.10 mL,
1.05 mmol). After being stirred for 24 h at 5 °C, the reaction mix-
ture was quenched by the addition of MeOH (1 mL) and the mix-
ture was stirred for another 4 h at room temperature. The
mixture was extracted with CH2Cl2 (3 ꢃ 10 mL), and the combined
organic extracts were washed with brine and dried over Na2SO4.
Solvent was removed under vacuum, and the residue was purified
by flash column chromatography (EtOAc/hexane = 1:8) to yield 14
25
(81 mg, 68%) as a colorless oil. ½aꢂD ¼ ꢀ19:0 ðc 1:5; CHCl3Þ. IR
(neat) mmax
: .
2930, 1745, 1453, 1256, 1152 cmꢀ1 1H NMR
4.4. (5S,6S)-1-Benzyl-5-benzyloxy-2-piperidinone-6-carboxylic
acid 12
(400 MHz, CDCl3): d 1.25–1.37 (m, 1H), 1.44–1.56 (m, 1H), 1.69
(ddd, J = 17.3, 7.7, 3.9 Hz, 1H), 1.97 (ddd, J = 11.3, 3.0, 3.0 Hz, 1H,
H-6), 2.10 (ddd, J = 17.3, 8.1, 4.0 Hz, 1H), 2.84 (ddd, J = 11.3, 3.9,
3.8 Hz, 1H, H-6), 3.05 (d, J = 8.3 Hz, 1H, H-2), 3.33 (d, J = 13.4 Hz,
1H, NCH2), 3.72 (s, 3H, OCH3), 3.74 (d, J = 13.4 Hz, 1H, NCH2),
3.77 (ddd, J = 8.3, 4.2, 4.2 Hz, 1H, H-3), 4.46 (d, J = 11.7 Hz, 1H,
OCH2), 4.59 (d, J = 11.7 Hz, 1H, OCH2), 7.20–7.40 (m, 10H, Ph–H).
13C NMR (100 MHz, CDCl3): d 22.28, 28.70, 50.64, 51.77, 60.23,
70.90, 70.94, 76.65, 127.12, 127.53 (2C), 127.63, 128.10 (2C),
128.25 (2C), 129.23 (2C), 137.40, 138.25, 173.05 (C@O). MS (ESI):
340 (M++1, 100). Anal. Calcd for C21H25NO3: C, 74.31; H, 7.42; N,
4.13. Found: C, 74.51; H, 7.36; N, 4.52.
To an ice-cold solution of NaIO4 (711 mg, 3.32 mmol) in EtOAc
(2.5 mL), CH3CN (4.5 mL) and H2O (2 mL) was added RuCl3
(0.05 M solution in H2O, 0.33 mL, 0.017 mmol). After 10 min, pipe-
ridinone 11 (120 mg, 0.33 mmol) in EtOAc (2 mL) was added. The
resultant mixture was stirred at 0 °C for 5 min and then poured
into H2O, and the phases were separated. The aqueous phase was
extracted with EtOAc (3 ꢃ 10 mL). The combined organic phases
were washed with brine, dried over Na2SO4 and concentrated. Sil-
ica gel column chromatography using EtOAc/MeOH (9:1) as eluent
25
gave 12 (79 mg, 70%) as a waxy solid. ½aꢂD ¼ ꢀ109:9 ðc 1:0; CHCl3Þ;
IR (film) mmax: 3450, 1693, 1650, 1495, 1450 cmꢀ1
.
1H NMR
4.7. (2S,3S)-3-Hydroxypipecolic acid 2
(400 MHz, CDCl3): d1.85–1.98 (m, 1H, H-4), 1.98–2.07 (m, 1H, H-
4), 2.57 (ddd, J = 18.0, 6.4, 1.0 Hz, 1H, H-3), 2.75 (ddd, J = 18.0,
6.8, 4.5 Hz, 1H, H-3), 3.68 (d, J = 15.3 Hz, 1H, NCH2), 4.07–4.12
(m, 1H, H-5), 4.22 (d, J = 1.2 Hz, 1H, H-6), 4.26 (d, J = 11.6 Hz, 1H,
OCH2), 4.31 (d, J = 11.6 Hz, 1H, OCH2), 5.68 (d, J = 15.3 Hz, 1H,
NCH2), 7.15–7.35 (m, 10H, Ph–H), 9.30 (br s, 1H, CO2H). 13C NMR
(100 MHz, CDCl3): d 23.24, 26.70, 49.15 (NCH2), 61.43 (OCH2),
70.37, 71.87, 127.37 (2C), 127.58, 127.75, 128.09 (2C), 128.38
(2C), 128.66 (2C), 135.85, 137.38, 171.38 (C@O), 171.73 (C@O).
MS (ESI): 340 (M++1, 100). Anal. Calcd for C20H21NO4: C, 70.78;
H, 6.24; N, 4.13. Found: C, 70.66; H, 6.51; N, 4.15.
To a solution of 14 (200 mg, 0.59 mmol) in THF (9 mL) and H2O
(3 mL) was added LiOHꢄH2O (125 mg, 2.98 mmol). The reaction
mixture was stirred at 70 °C for 3 h. The reaction mixture was neu-
tralized by addition of 10% solution of KHSO4 and diluted with
CH2Cl2. The organic phase was separated and the aqueous phase
extracted with CH2Cl2 (3 ꢃ 10 mL). The combined organic extracts
were washed with brine, dried over Na2SO4, and concentrated to a
crude product.
To a mixture of Pd(OH)2/C (110 mg, 20% Pd) in ethanol (5 mL)
was added this crude product in EtOH (3 mL). After being stirred
at room temperature under an atmosphere of H2 for 72 h, the mix-
ture was filtered over Celite and concentrated to provide 2 (51 mg,
4.5. (5S,6S)-1-Benzyl-5-benzyloxy-2-piperidinone-6-carboxylic
acid methyl ester 13
25
51%) as a white solid. ½aꢂD ¼ þ13:3 ðc 0:7; 10% aq HClÞ [lit.11
20
½aꢂD ¼ þ12:9 ðc 0:23; 10% aq HClÞ]. Mp: 228–235 °C (lit.11 mp
To an ice-cold solution of 12 (300 mg, 0.88 mmol) in dry MeOH
(8 mL) was added SOCl2 (0.14 mL, 1.92 mmol). After being stirred
for 24 h at room temperature, the reaction mixture was quenched
by the addition of saturated aqueous NaHCO3 solution (5 mL) and
230–238 °C). IR (film) mmax: 3410, 1685, 1450, 1137 cmꢀ1 1H
.
NMR (400 MHz, D2O): d 1.60–1.66 (m, 2H), 1.92–1.95 (m. 2H),
2.80–2.95 (m, 1H), 3.80–3.83 (m, 1H), 4.10–4.15 (m, 1H), 4.33 (br
s, 1H). 13C NMR (100 MHz, D2O): d 20.12, 30.05, 46.46, 62.10,

L.-X. Liu et al. / Tetrahedron: Asymmetry 19 (2008) 1200–1203
1203
66.38, 176.46. MS (ESI): 146 (M++1, 100). HRESIMS calcd for
[C6H11NO3+H]+: 146.0817; Found: 146.0818.
4. Scott, J. D.; Tippie, T. N.; Williams, R. M. Tetrahedron Lett. 1998, 39, 3659–3662.
5. For a recent review, see: Nemr, A. E. Tetrahedron 2000, 56, 8579–8629.
6. Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. Rev. 2000, 100, 4683–4696.
7. Liu, L.-X.; Huang, P.-Q. Tetrahedron: Asymmetry 2006, 17, 3265–3272. and
references cited therein.
8. (a) Huang, P.-Q.; Liu, L.-X.; Wei, B.-G.; Ruan, Y.-P. Org. Lett. 2003, 5, 1927–1930;
(b) Huang, P.-Q.; Wei, B.-G.; Ruan, Y.-P. Synlett 2003, 1663–1667; (c) Liu, L.-X.;
Ruan, Y.-P.; Guo, Z.-Q.; Huang, P.-Q. J. Org. Chem. 2004, 69, 6001–6009; (d)
Ruan, Y.-P.; Wei, B.-G.; Xu, X.-Q.; Liu, G.; Yu, D.-S.; Liu, L.-X.; Huang, P.-Q.
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Acknowledgment
The authors are grateful to the NSF of China (20772099) for
financial support.
9. For recent references on the syntheses of 3-hydroxypipecolic acid, see: (a) Kim,
I. S.; Oh, J. S.; Zee, O. P.; Jung, Y. H. Tetrahedron 2007, 63, 2622–2633; (b) Kim, I.
S.; Ji, Y. J.; Jung, Y. H. Tetrahedron Lett. 2006, 47, 7289–7293; (c) Liang, N.; Datta,
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