A concise approach to homochiral 3,4-dihydroxyglutamic acids

Article abstract of DOI:10.1016/S0040-4020(02)01218-8

A concise diastereoselective synthesis of 3,4-dihydroxyglutamic acids was investigated. The key reaction in this synthesis is stereoselective cyanation of an optically active N-acyliminium intermediate derived from L- or D-tartaric acid. The stereoselectivity in the cyanation reaction could be controlled by the protective group of the hydroxyl function. Deprotection of the obtained cyanolactam followed by acidic hydrolysis afforded the desired 3,4-dihydroxyglutamic acids. The 3,4-dihydroxyglutamic acids obtained in this synthesis are (2S,3S,4R)-, (2R,3S,4R)-, (2S,3R,4S)-, and (2R,3R,4S)-isomers and the three latter compounds are novel derivatives of glutamic acids.

Full text of DOI:10.1016/S0040-4020(02)01218-8

Tetrahedron 58 (2002) 9359–9363
A concise approach to homochiral 3,4-dihydroxyglutamic acids
*
Makoto Oba, Shinichi Koguchi and Kozaburo Nishiyama
*
Department of Material Science and Technology, Tokai University, 317 Nishino, Numazu, Shizuoka 410-0395, Japan
Received 9 September 2002; accepted 27 September 2002
Abstract—A concise diastereoselective synthesis of 3,4-dihydroxyglutamic acids was investigated. The key reaction in this synthesis is
stereoselective cyanation of an optically active N-acyliminium intermediate derived from L- or D-tartaric acid. The stereoselectivity in the
cyanation reaction could be controlled by the protective group of the hydroxyl function. Deprotection of the obtained cyanolactam followed
by acidic hydrolysis afforded the desired 3,4-dihydroxyglutamic acids. The 3,4-dihydroxyglutamic acids obtained in this synthesis are
(2S,3S,4R)-, (2R,3S,4R)-, (2S,3R,4S)-, and (2R,3R,4S)-isomers and the three latter compounds are novel derivatives of glutamic acids. q 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
In our preliminary communication,7 we reported a concise
diastereoselective synthesis of (2S,3S,4R)-3,4-dihydroxy-
glutamic acid, in which L-tartaric acid was adopted as the
starting material because the acid already contains the
required two hydroxyl groups with established configur-
ations. We here disclose a concise approach to (2S,3R,4S)-
3,4-dihydroxyglutamic acid as well as the (2S,3S,4R)-
isomer. In this synthesis, the corresponding (2R,3R,4S)
and (2R,3S,4R)-isomers were also obtained as concomitant
products.
Because of the implication of glutamate receptors in brain
ischemia, epilepsy, and neurodegenerative syndromes such
as Alzheimer’s, Parkinson’s, and Huntington’s diseases,1 a
large number of analogues of glutamic acid have been
prepared to probe the physiological role of the receptors.2
Most of the reported glutamic acid analogues are alkyl
substituted derivatives including conformationally
restricted cyclic or bicyclic compounds and some of them
exhibit potent affinity to specific glutamate receptors and are
expected to have therapeutic applications.
On the other hand, hydroxylated glutamic acid derivatives
are less studied despite the potential of the high-affinity
ligands based on their additional ability of intra- and
intermolecular hydrogen bonding. 3,4-Dihydroxyglutamic
acid is a naturally occurring amino acid, which was isolated
for the first time from the seeds of Lepidum sativum and the
leaves of Rheum rhaponticum over 40 years ago;3 however,
the relative and absolute configurations of the three chiral
centers are unknown. Although some reports on the
preparation of 3- and 4-hydroxyglutamic acids have been
published,4 only two methods for the preparation of
enantiopure (2S,3S,4S)5 and (2S,3S,4R)-3,4-dihydroxy-
glutamic acids6 have appeared in the literature, and the
former compound was found to be a selective agonist of
mGluR1. However, the methods require multistep synthesis
from the commercially available starting material and lack
applicability to other diastereomers. Therefore, we set out to
devise a simple and general approach to all diastereomers.
2. Results and discussion
The optically active cyclic imides8 1a and 1b derived from
L-tartaric acid were converted to acetoxylactams 2a and 2b
by reduction with sodium borohydride followed by
acetylation (Scheme 1). The acetylation of the incipient
hydroxylactams was necessary for the subsequent cyanation
reaction. Table 1 shows the representative results of
stereoselective cyanation of the acetoxylactams 2a and 2b.
When a solution of lactam 2a and tributyltin cyanide9
(1.5 equiv.) in toluene was treated with trifluoroborane
etherate (2 equiv.) at room temperature, a 90:10 mixture of
the desired cyanolactams10 4a and 5a was obtained in 94%
yield (entry 4). The choice of tributyltin cyanide over
trimethylsilyl cyanide and toluene over dichloromethane as
the solvent proved to be advantageous for the stereoselec-
tive cyanation of lactam 2a (entries 1–4). Other Lewis acids
or lower reaction temperature did not improve the
selectivity. The stereochemistry of cyanolactams 4a and
5a was assigned according to the observed vicinal coupling
constants J4,5¼6.7 and 4.4 Hz, respectively. In similar
systems,11–13 the cis coupling constant is usually larger than
that of the trans isomer. Final confirmation of the
Keywords: 3,4-dihydroxyglutamic acid; N-acyliminium intermediate;
cyanation; tartaric acid.
*
Corresponding authors. Tel.: þ81-559-68-1111; fax: þ81-559-68-1155;
e-mail: makoto@wing.ncc.u-tokai.ac.jp
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01218-8

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M. Oba et al. / Tetrahedron 58 (2002) 9359–9363
Scheme 1. (i) NaBH4; (ii) Ac2O in pyridine; (iii) BF3–OEt2; (iv) Me3SiCN or Bu3SnCN; (v) Ce(NH4)2(NO2)6; (vi) 6 M HCl, 1108C, then Dowex 50W-W8.
stereochemistry was provided by transformation into 3,4-
dihydroxyglutamic acids 6 and 7 (vide infra).
The diastereomeric cyanolactams 4 and 5 can be easily
separated by flash column chromatography on silica gel
when the O-protective group is a TBDMS group. The major
isomer 4a was then treated with diammonium cerium nitrate
to remove the N-PMB protecting group followed by 6 M
HCl at 1108C. The crude product was purified by ion
exchange column chromatography (Dowex 50W-X8) to
furnish (2S,3S,4R)-3,4-dihydroxyglutamic acid (6)6 in 73%
yield based on 4a. The conversion of the minor isomer 5a
was also carried out and the diastereomeric (2R,3S,4R)-3,4-
dihydroxyglutamic acid (7), a novel glutamic acid deriva-
tive, was obtained in 58% yield.
There are some reports on the Lewis acid-promoted addition
of tin and silicon nucleophiles to the N-acyliminium ion syn
to the adjacent O-TBDMS group,12–14 revealing that this
stereochemical outcome is not ruled by steric effects.
Although the actual cause of this unexpected stereo-
selectivity has not been established, Cieplak-type stereo-
electronic effect15 or the exterior frontier orbital extension
model (EFOE model)16 may be necessary to explain the
observed facial diastereoselection.
On the other hand, the stereoselectivity in the cyanation
reaction of acetoxylactam 2b, in which the O-protective
group is an acetyl group, is completely reversed, affording
an 18:82 mixture of cyanolactams 4b and 5b in 80% yield
(entry 5). The predominant formation of 5b can be attributed
to the normal steric effect between the cyanating reagent and
the neighboring acetoxy group. The use of toluene as the
solvent (entry 6) or tributyltin cyanide as the cyanating
reagent gave no improvement in this case.
In order to obtain the corresponding (2S,3R,4S)-isomer, the
enantiomer of 3,4-dihydroxyglutamic acid 7, as a major
product, we next carried out the stereoselective cyanation of
triacetate 8 derived from D-tartaric acid (Scheme 2).
Treatment of acetoxylactam 8 with trimethylsilyl cyanide
in the presence of trifluoroborane etherate gave cyanolactam
10 in 93% yield as an 80:20 mixture of diastereomers. This
diastereomeric mixture was difficult to separate completely
by column chromatography so the O-protective group was
once transformed into a TBDMS group. After chromato-
graphic separation, diastereomers 11 and 12, obtained in 53
and 22% yields, respectively, were independently treated
with diammonium cerium nitrate followed by acidic
hydrolysis to afford novel (2S,3R,4S) and (2R,3R,4S)-3,4-
dihydroxyglutamic acids (13) and (14) in 40 and 35%
yields, respectively.
These results indicate that the face-selectivity of the
nucleophilic cyanation toward the N-acyliminium inter-
mediate 3 can be controlled by the O-protective group.
Thaning and Wistrand reported similar stereocontrolled
reaction with 3 or 4-substituted N-acylpyrrolidinium ions.13
In summary, we have demonstrated a concise diastereose-
lective synthesis of 3,4-dihydroxyglutamic acids based on
the stereoselective cyanation of the chiral N-acyliminium
ion derived from L- or D-tartaric acid. It was found that the
stereoselectivity in the cyanation reaction could be con-
trolled by the O-protective group. From O-TBDMS
acetoxylactam 2a derived from L-tartaric acid, (2S,3S,4R)-
3,4-dihydroxyglutamic acid (6) was obtained as a major
product, whereas the cyanation of O-acetyl lactam 8 derived
from D-tartaric acid led mainly to the corresponding
(2S,3R,4S)-isomer 13. Since the minor cyanolactams 5a
Table 1. Stereoselective cyanation of optically active acetoxylactam 2
Entry Acetoxy-lactam Metal cyanide Solvent Selectivity Yield
(4/5)a
(%)
1
2
3
4
5
6
2a
2a
2a
2a
2b
2b
Me3SiCN
Me3SiCN
Bu3SnCN
Bu3SnCN
Me3SiCN
Me3SiCN
CH2Cl2 80/20
94
96
98
94
80
82
Toluene 84/16
CH2Cl2 89/11
Toluene 90/10
CH2Cl2 18/82
Toluene 23/77
a
Determined by 1H NMR spectroscopy.

M. Oba et al. / Tetrahedron 58 (2002) 9359–9363
9361
Scheme 2. (i) BF3–OEt2; (ii) Me3SiCN; (iii) AcCl, EtOH; (iv) TBDMS–Cl, imidazole; (v) Ce(NH4)2(NO2)6; (vi) 6 M HCl, 1108C, then Dowex 50W-X8.
and 12 could be easily isolated from the reaction mixture,
the diastereomeric (2R,3S,4R)- and (2R,3R,4S)-3,4-dihydro-
xyglutamic acids 7 and 14 were also obtained in an
enatiomerically pure form. Among them, the amino acids 7,
13, and 14 are novel derivatives of hydroxyglutamic acids.
7.14 (d, J¼9 Hz, 2H). 13C NMR (CDCl3) d 25.19, 25.15,
25.06, 24.57, 17.57, 17.96, 20.52, 25.35, 25.52, 43.63,
55.00, 76.58, 77.10, 86.62, 113.77, 128.06, 129.12, 158.93,
170.09, 172.27. MS (CI) m/z 524 (MHþ). HRMS (EI,
70 eV) m/z 508.2519 [(M2Me)þ, calcd for C25H42NO6Si2
508.2551].
3.1.2. (3R,4S,5R)-3,4-Bis[(tert-butyldimethylsilyl)oxy]-5-
cyano-1-(4-methoxybenzyl)-2-pyrrolidinone (4a) and
(3R,4S,5S)-3,4-bis[(tert-butyldimethylsilyl)oxy]-5-cyano-
1-(4-methoxybenzyl)-2-pyrrolidinone (5a). To a solution
of acetoxylactam 2a (520 mg, 1.00 mmol) and tributyltin
cyanide (480 mg, 1.50 mmol) in toluene (20 mL) was added
a solution of boron trifluoride etherate (280 mg, 2.00 mmol)
in toluene (1 mL) at 08C under an argon atmosphere, and the
reaction mixture was stirred for 5 min. After it was stirred at
room temperature for 1 h, the reaction mixture was
quenched with saturated aqueous Na2CO3 and extracted
with ethyl acetate. The organic layer was dried over MgSO4
and concentrated in vacuo. The crude product was purified
by column chromatography on silica gel (hexane/ethyl
acetate¼50:50) to give the title compound 5a (50.0 mg,
3. Experimental
3.1. General
1H and 13C NMR spectra were recorded at 400 and
100 MHz, respectively. All chemical shifts are reported as
d values (ppm) relative to residual chloroform (dH 7.26),
sodium 3-(trimethylsilyl)[2,2,3,3-D4]propionate (dH 0.00
and dc 0.00), or the central peak of CDCl3 (dc 77.00). High-
resolution mass spectra (HRMS) were determined using
perfluorokerosene as an internal standard. Optical rotations
were measured on a HORIBA SEPA-200 polarimeter.
3.1.1. (3R,4R)-3,4-Bis[(tert-butyldimethylsilyl)oxy]-5-
acetoxy-1-(4-methoxybenzyl)-2-pyrrolidinone (2a). To a
solution of imide 1a (14.4 g, 30.0 mmol) in methanol
(300 mL) was added sodium borohydride (5.67 g,
150 mmol) at 08C. After it was stirred for 1 h, the reaction
mixture was quenched with saturated aqueous NaHCO3 and
extracted with dichloromethane. The organic layer was
dried over MgSO4 and evaporated to dryness to give a
hydroxylactam as a white solid. To a solution of the
hydroxylactam in pyridine (50 mL) was added acetic
anhydride (15.3 g, 150 mmol), and the reaction mixture
was stirred at room temperature overnight. After evapor-
ation of the solvent, the residue was extracted with
chloroform. The organic layer was washed successively
with 1 M HCl and saturated aqueous NaHCO3, dried over
MgSO4, and evaporated. The crude product was purified by
column chromatography on silica gel (hexane/ethyl
acetate¼50:50) to give the title compounds 2a (14.0 g,
1
10%) as a colorless oil. H NMR (CDCl3) d 0.10 (s, 3H),
0.12 (s, 3H), 0.16 (s, 3H), 0.21 (s, 3H), 0.84 (s, 9H), 0.93 (s,
9H), 3.75 (d, J¼4 Hz, 1H), 3.78 (s, 3H), 3.91 (d, J¼15 Hz,
1H), 4.06 (d, J¼4 Hz, 1H), 4.32 (dd, J¼4, 4 Hz, 1H), 5.14
(d, J¼15 Hz, 1H), 6.86 (d, J¼9 Hz, 2H), 7.18 (d, J¼9 Hz,
2H). 13C NMR (CDCl3) d 25.02, 24.79 (2C), 24.41,
17.58, 18.02, 25.42, 25.56, 44.40, 52.38, 55.15, 76.48,
76.68, 114.32, 115.50, 126.15, 129.75, 159.51, 170.38. MS
(CI) m/z 491 (MHþ). HRMS (EI, 30 eV) m/z 475.2455
[(M2Me)þ, calcd for C24H39N2O4Si2 475.2448].
Further elution with a mixture of hexane and ethyl acetate
(50:50) gave the corresponding (3R,4S,5R)-isomer 4a
1
(430 mg, 88%) as a colorless oil. H NMR (CDCl3) d 0.07
(s, 3H), 0.11 (s, 3H), 0.17 (s, 3H), 0.23 (s, 3H), 0.91 (s, 9H),
0.93 (s, 9H), 3.80 (s, 3H), 3.96 (d, J¼15 Hz, 1H), 4.09 (d,
J¼7 Hz, 1H), 4.14 (dd, J¼7, 7 Hz, 1H), 4.31 (d, J¼7 Hz,
1H), 4.99 (d, J¼15 Hz, 1H), 6.88 (d, J¼9 Hz, 2H), 7.19 (d,
J¼9 Hz, 2H). 13C NMR (CDCl3) d 24.99, 24.90, 24.85,
24.40, 17.74, 18.15, 25.50, 25.59, 44.94, 50.64, 55.20,
73.40, 75.77, 114.38, 114.51, 125.75, 129.91, 159.65,
1
89%) as a colorless oil. H NMR (CDCl3) d 0.01 (s, 3H),
0.06 (s, 3H), 0.14 (s, 3H), 0.19 (s, 3H), 0.81 (s, 9H), 0.91 (s,
9H), 1.90 (s, 3H), 3.75 (s, 3H), 3.96 (dd, J¼3, 2 Hz, 1H),
4.02 (d, J¼3 Hz, 1H), 4.15 (d, J¼15 Hz, 1H), 4.61 (d,
J¼15 Hz, 1H), 5.74 (d, J¼2 Hz, 1H), 6.80 (d, J¼9 Hz, 2H),

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M. Oba et al. / Tetrahedron 58 (2002) 9359–9363
170.42. MS (CI) m/z 491 (MHþ). HRMS (EI, 30 eV) m/z
475.2491 [(M2Me)þ, calcd for C24H39N2O4Si2 475.2448].
solution of boron trifluoride etherate (2.84 g, 20.0 mmol) in
dichloromethane (10 mL) at 08C under an argon atmos-
phere, and the reaction mixture was stirred for 5 min. After
it was stirred at room temperature for 1 h, the reaction
mixture was quenched with saturated aqueous Na2CO3 and
extracted with dichloromethane. The organic layer was
dried over MgSO4 and concentrated in vacuo. The crude
product was purified by column chromatography on silica
gel (hexane/ethyl acetate¼50:50) to give the title com-
pounds 10 (3.22 g, 93%) as a partially separable mixture of
3.1.3. (2S,3S,4R)-3,4-Dihydroxyglutamic acid (6). To a
suspension of cyanolactam 4a (4.80 g, 11.0 mmol) and
diammonium cerium (IV) nitrate (12.0 g, 22.0 mmol) in
acetonitrile (33 mL) was added water (11 mL) at room
temperature, and the resulting mixture was stirred for 4 h.
The reaction mixture was then diluted with ethyl acetate,
washed with water, and dried over MgSO4. After removal of
the solvent, the residue was hydrolyzed in refluxing 6 M
HCl (300 mL) overnight. The cooled aqueous solution was
washed with chloroform and concentrated to dryness. The
residue was submitted to ion exchange column chromato-
graphy on Dowex 50W-X8 to furnish the title compound 6
(1.43 g, 73%) as white powder, [a]2D5¼þ8.59 (c 1.08, 18%
HCl) (lit,6 [a]D28¼þ8.5 (c 1.08, 18% HCl)). 1H NMR (D2O)
d 3.96 (d, J¼3 Hz, 1H), 4.24 (d, J¼2 Hz, 1H), 4.51 (dd,
J¼3, 2 Hz, 1H). 13C NMR (D2O) d 60.9, 72.4, 77.6, 175.4,
180.4. MS (FAB) m/z 180 (MHþ).
1
diastereomers. Major isomer: H NMR (CDCl3) d 2.03 (s,
3H), 2.12 (s, 3H), 3.74 (s, 3H), 3.97 (d, J¼15 Hz, 1H), 4.00
(d, J¼5 Hz, 1H), 5.11 (d, J¼15 Hz, 1H), 5.28 (d, J¼5 Hz,
1H), 5.42 (dd, J¼5, 5 Hz, 1H), 6.84 (d, J¼8 Hz, 2H), 7.17
(d, J¼8 Hz, 2H). 13C NMR (CDCl3) d 20.10, 20.16, 44.83,
50.30, 55.05, 72.75, 72.81, 114.06, 114.34, 125.04, 129.88,
159.61, 166.03, 169.34, 169.56. HRMS (EI, 70 eV) m/z
346.1153 (Mþ, calcd for C17H18N2O6 346.1165). Minor
isomer: 1H NMR (CDCl3) d 2.07 (s, 6H), 3.68 (s, 3H), 3.98
(d, J¼15 Hz, 1H), 4.60 (d, J¼7 Hz, 1H), 4.87 (d, J¼15 Hz,
1H), 5.22 (dd, J¼7, 7 Hz, 1H), 5.47 (d, J¼7 Hz, 1H), 6.79
(d, J¼8 Hz, 2H), 7.13 (d, J¼8 Hz, 2H). 13C NMR (CDCl3) d
19.93, 19.98, 45.07, 48.43, 54.80, 69.29, 72.06, 112.76,
114.10, 124.65, 129.73, 159.46, 165.52, 169.27, 179.75.
HRMS (EI, 70 eV) m/z 346.1133 (Mþ, calcd for
C17H18N2O6 346.1165).
3.1.4. (2R,3S,4R)-3,4-Dihydroxyglutamic acid (7).
According to the procedure for the preparation of the
compound 6, deprotection and hydrolysis of the cyano-
lactam 5a (670 mg, 1.34 mmol) gave the title compound 7
(140 mg, 58%) as white powder, [a]2D5¼-3.80 (c 1.08, 18%
1
HCl). H NMR (D2O) d 4.05 (d, J¼5 Hz, 1H), 4.14 (d,
J¼2 Hz, 1H), 4.54 (dd, J¼5, 2 Hz, 1H). 13C NMR (D2O) d
3.1.7. (3S,4R,5R)-3,4-Bis[(tert-butyldimethylsilyl)oxy]-5-
cyano-1-(4-methoxybenzyl)-2-pyrrolidinone (11) and
(3S,4R,5S)-3,4-bis[(tert-butyldimethylsilyl)oxy]-5-cyano-
1-(4-methoxybenzyl)-2-pyrrolidinone (12). To a solution
of cyanolactam 10 (3.22 g, 9.33 mmol) in ethanol (47 mL)
was added acetyl chloride (2.19 g, 27.9 mmol), and the
solution was stirred at 508C for 2 h. After evaporation of the
solvent, the residue was dissolved in N,N-dimethylforma-
mide (47 mL). To the solution was added imidazole (2.85 g,
41.9 mmol) and tert-butyldimethylchlorosilane (4.21 g,
27.9 mmol), and the solution was stirred at room tempera-
ture overnight. The reaction mixture was then diluted with
ethyl acetate, washed with water, and dried over MgSO4.
After removal of the solvent, the residue was chromato-
graphed on silica gel using a mixture of hexane and ethyl
acetate (50:50) as an eluent. The fast fraction contained
compound 11 (2.43 g, 53%), and further elution gave
compound 12 (1.00 g, 22%). The spectral data of com-
pounds 11 and 12 are identical with those of compounds 5a
and 4a, respectively.
61.9, 71.4, 76.2, 174.5, 180.4. MS (FAB) m/z 180 (MHþ).
3.1.5. (3S,4S)-3,4,5-Triacetoxy-1-(4-methoxybenzyl)-2-
pyrrolidinone (8). To a solution of (3S,4S)-3,4-diacetoxy-
1-(4-methoxybenzyl)-2,5-pyrrolidinedione (7.87 g, 16.4
mmol), derived from D-tartaric acid, in methanol
(150 mL) was added sodium borohydride (3.14 g,
82.1 mmol) at 08C. After it was stirred for 1 h, the reaction
mixture was quenched with saturated aqueous NaHCO3 and
extracted with dichloromethane. The organic layer was
dried over MgSO4 and evaporated to dryness to give a
hydroxylactam as a white solid. To a solution of the
hydroxylactam in pyridine (200 mL) was added acetic
anhydride (8.38 g, 82.1 mmol), and the reaction mixture
was stirred at room temperature overnight. After evapor-
ation of the solvent, the residue was extracted with
chloroform. The organic layer was washed successively
with 1 M HCl and saturated aqueous NaHCO3, dried over
MgSO4, and evaporated. The crude product was purified by
column chromatography on silica gel (hexane/ethyl
acetate¼50:50) to give the title compounds 8 (8.14 g,
3.1.8. (2S,3R,4S)-3,4-Dihydroxyglutamic acid (13).
According to the procedure for the preparation of compound
6, deprotection and hydrolysis of cyanolactam 11 (183 mg,
3.83 mmol) gave the title compound 13 (280 mg, 40%) as
white powder. The spectral data of compound 13 is identical
with those of the compounds 7, [a]2D5¼þ4.07 (c 1.08, 18%
HCl).
1
94%) as a colorless oil. H NMR (CDCl3) d 1.92 (s, 3H),
2.03 (s, 3H), 2.14 (s, 3H), 3.75 (s, 3H), 4.18 (d, J¼15 Hz,
1H), 4.61 (d, J¼15 Hz, 1H), 5.16 (dd, J¼4, 2 Hz, 1H), 5.30
(d, J¼4 Hz, 1H), 5.99 (d, J¼2 Hz, 1H), 6.81 (d, J¼9 Hz,
2H), 7.14 (d, J¼9 Hz, 2H). 13C NMR (CDCl3) d 19.97 (2 C),
20.05, 43.74, 54.71, 72.75, 75.50, 82.90, 113.62, 126.88,
129.20, 158.88, 167.18, 169.05, 169.12, 169.22. HRMS
(EI, 30 eV) m/z 379.1288 (Mþ, calcd for C18H21NO8
379.1267).
3.1.9. (2R,3R,4S)-3,4-Dihydroxyglutamic acid (14).
According to the procedure for the preparation of compound
6, deprotection and hydrolysis of cyanolactam 12 (2.33 g,
4.95 mmol) gave the title compound 14 (520 mg, 60%) as
white powder. The spectral data of compound 14 is identical
with those of compounds 6, [a]2D5¼28.26 (c 1.08, 18%
HCl).
3.1.6. (3S,4R)-3,4-Diacetoxy-5-cyano-1-(4-methoxyben-
zyl)-2-pyrrolidinone (10). To a solution of acetoxylactam
8 (3.78 g, 10.0 mmol) and trimethylsilyl cyanide (1.48 g,
15.0 mmol) in dichloromethane (200 mL) was added a

M. Oba et al. / Tetrahedron 58 (2002) 9359–9363
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Acher, F.; Prezeau, L.; Brabet, I.; Pin, J.-P.; Dodd, R. H.
Bioorg. Med. Chem. Lett. 2000, 10, 129–133.
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