Facile synthesis of 3-hydroxyglutamic acids via cyanation of chiral N-acyliminium cation derived from (S)-malic acid

Article abstract of DOI:10.1080/00397910500278446

Facile synthesis of 3-hydroxyglutamic acids via cyanation of an N -acyliminium intermediate derived from (S)-malic acid is described. The chiral cyclic imide derived from (S)-malic acid was converted to an acetoxylactam by reduction with sodium borohydrid

Full text of DOI:10.1080/00397910500278446

This article was downloaded by: [Northeastern University]
On: 03 December 2014, At: 17:07
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Facile Synthesis of
3‐Hydroxyglutamic Acids
via Cyanation of Chiral
N‐Acyliminium Cation Derived
From (S)‐Malic Acid
Makoto Oba a , Atsushi Mita a , Yoshinori Kondo a
Kozaburo Nishiyama a
a Department of Materials Chemistry , Tokai
University , Shizuoka, Japan
&
Published online: 21 Aug 2006.
To cite this article: Makoto Oba , Atsushi Mita , Yoshinori Kondo & Kozaburo
Nishiyama (2005) Facile Synthesis of 3‐Hydroxyglutamic Acids via Cyanation of Chiral
N‐Acyliminium Cation Derived From (S)‐Malic Acid, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:23,
2961-2966
To link to this article: http://dx.doi.org/10.1080/00397910500278446
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views

expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 35: 2961–2966, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500278446
Facile Synthesis of 3-Hydroxyglutamic
Acids via Cyanation of Chiral
N-Acyliminium Cation Derived
From (S)-Malic Acid
Makoto Oba, Atsushi Mita, Yoshinori Kondo, and
Kozaburo Nishiyama
Department of Materials Chemistry, Tokai University, Shizuoka, Japan
Abstract: Facile synthesis of 3-hydroxyglutamic acids via cyanation of an
N-acyliminium intermediate derived from (S)-malic acid is described. The chiral
cyclic imide derived from (S)-malic acid was converted to an acetoxylactam by
reduction with sodium borohydride followed by acetylation. The obtained acetoxy-
lactam was treated with trimethylsilyl cyanide in the presence of boron trifluoride
etherate to give the corresponding cyanolactam in high yield, even though the diaster-
eoselectivity of the cyanation reaction was moderate. The diastereomers of the cyano-
lactam were chromatographically separable and were independently converted to
(2R,3S)- and (2S,3S)-3-hydroxyglutamic acids.
Keywords: cyanation, 3-hydroxyglutamic acid, malic acid, N-acyliminium cation
Recently, substituted L-glutamic acids have received a great deal of attention
because of their diverse biological function as selective ligands for the specific
glutamate receptor. Most of the reported L-glutamic acid analogues are alkyl-
substituted or are cyclic derivatives and some of them are recognized as useful
pharmacological tools.[1] However, the corresponding hydroxylated deriva-
tives have been less studied.
Received in Japan June 4, 2005
Address correspondence to Makoto Oba, Department of Materials Chemistry, Tokai
University, Shizuoka 410 0395, Japan. Fax: 81-55-968-1155; E-mail: makoto@wing.
ncc.u-tokai.ac.jp
2961

2962
M. Oba et al.
We have recently reported concise and general methods for the stereose-
lective synthesis of eight possible stereoisomers of 3,4-dihydroxyglutamic
acid via cyanation of optically active N-acyliminium cations derived from
tartaric acid.[2] As an extension of the N-acyliminium methodology for the
stereoselective synthesis of hydroxylated amino acids, we describe herein a
facile synthesis of 3-hydroxyglutamic acids.
Recently, 3-hydroxyglutamic acids were found to have important bio-
logical effects on a neuron of an African giant snail.[3] Further interest stems
from their usefulness as chiral building blocks for the asymmetric synthesis
of biologically active compounds.[4] Among the four possible stereoisomers
of 3-hydroxyglutamic acids, the (2S,3R)-isomer was first obtained as a
component of the peptide antibiotic S-520.[5] Later, some methods have been
developed for the stereoselective synthesis of 3-hydroxyglutamic acids.[6]
RESULTS AND DISCUSSION
The synthetic course of (2R,3S)- and (2S,3S)-3-hydroxyglutamic acids is
illustrated in Scheme 1. The starting cyclic imide 1a was readily accessible
from (S)-malic acid according to the reported procedure.[7] Cleavage of
the O-acetyl group of the imide 1a followed by O-silylation with tert-
butyldimethylsilyl (TBDMS) group afforded a novel chiral imide 1b in
55% yield over two steps. Conversion of the imide 1 into acetoxylactam 2
was carried out by regiospecific reduction of the imide carbonyl group
with sodium borohydride and subsequent O-acetylation of the intermediary
hemiaminal. The acetoxylactam 2 was obtained as an inseparable mixture
of diastereomers and was then subjected to the cyanation reaction; the rep-
resentative results are listed in Table 1. When a solution of lactam 2b
Scheme 1. Preparation of (2R,3S)- and (2R,3S)-3-hydroxyglutamic acids (4). Reagents
and conditions: a) AcCl, EtOH; b) tert-BuMe2SiCl, imidazole, 55% (two steps); c)
NaBH4, MeOH; d) AcCl, pyridine, 2b: 73% (two steps); e) Me3SiCN, BF3-OEt2,
CH2Cl2, cis-3b: 56%, trans-3b: 42%; f) Ce(NH4)2(NO3)6, MeCN; g) 6 M HCl reflux,
then Dowex 50W-X8, (2R,3S)-4: 43%, (2S,3S)-4: 40%. PMB ¼ 4-methoxybenzyl.

3-Hydroxyglutamic Acid Synthesis
2963
Table 1. Preparation of cyanolactam 3 from acetoxylactam 2
Metal
cyanide
Diastereoselectivity
(cis : trans)
Yield,
%
Entry
R
Solvent
1
2
3
4
TBDMS
TBDMS
TBDMS
Ac
Me3SiCN
Me3SiCN
Bu3SnCN
Me3SiCN
CH2Cl2
Toluene
Toluene
CH2Cl2
57 : 43
73 : 27
58 : 42
39 : 61
98
70
40
98
(R ¼ TBDMS), trimethylsilyl cyanide, and boron trifluoride diethyl etherate
in dichloromethane was stirred at 08C for 1 h, cyanolactam 3b was obtained
in 98% yield as a 57 : 43 mixture of cis and trans isomers (entry 1). Similar
treatment in toluene slightly improved the cis selectivity but the chemical
yield was lowered (entry 2). The choice of tributyltin cyanide as the
cyanating reagent and toluene as the solvent, the best conditions employed
for the cis selective cyanation in our previous study,[2a,b] resulted in disap-
pointing results in the present case (entry 3). No significant improvement
in the diastereoselectivity was observed when the Lewis acid was changed,
and lower reaction temperatures greatly lowered the chemical yield. Conver-
sely, the diastereoselectivity in the cyanation of acetoxylactam 2a (R ¼ Ac)
was reversed, giving 98% yield of cyanolactam 3a as a 39 : 61 mixture of cis
and trans isomers (entry 4). Similar reversal in diastereoselectivity depending
on the adjacent O-protective group is often observed in the Lewis acid–
promoted addition of tin and silicon nucleophiles to the N-acyliminium
cation;[8] however, the explanation of the about-face in selectivity awaits
theoretical verification.
The diastereomers of the cyanolactam 3b (R ¼ TBDMS) could be easily
separated by flash column chromatography on silica gel and, in the case of
entry 1, cis- and trans-3b were isolated in 56 and 42% yields, respectively.
The major isomer cis-3b was then treated with ammonium cerium(IV)
nitrate (CAN) to remove the 4-methoxybenzyl (PMB) protecting group and
hydrolyzed in refluxing 6 M HCl. The standard ion-exchange operation on
the hydrolysate with Dowex 50W-X8 furnished (2R,3S)-3-hydroxyglutamic
acid (4) in 43% yield (two steps). Similar treatment of trans-3b afforded
(2S,3S)-4 in 40% yield (two steps). The structures of the obtained 3-hydroxy-
glutamic acids, (2R,3S)- and (2S,3S)-4, were confirmed by comparison of the
1H NMR spectra with those reported in the literature.[6c]
In conclusion, we have demonstrated a concise synthesis of (2R,3S)-
and (2S,3S)-3-hydroxyglutamic acids via cyanation of an optically active
N-acyliminium cation derived from (S)-malic acid. Although we have not
employed (R)-malic acid as a starting material, we can see no reason
why such reactions should not proceed likewise to give the corresponding
(3R)-isomers. Thus, the present protocol provides a facile approach to four
possible diastereomers of the 3-hydroxyglutamic acids.

2964
M. Oba et al.
EXPERIMENTAL
1H and 13C NMR spectra were measured at 400 and 100 MHz, respectively.
All chemical shifts are reported as d values (ppm) relative to residual chloro-
form (dH 7.26), HDO (dH 4.65), or the central peak of deuteriochloroform (dC
77.0). High-resolution mass spectra (HRMS) were determined using perfluoro-
kerosene as an internal standard. Solvents and reagents were of commercial
grade and were purified if necessary.
3-(tert-Butyldimethylsiloxy)-1-(4-methoxybenzyl)-2,5-pyrrolidinedione (1b).
Acetyl chloride (54.0 g, 69.0 mmol) was added to a solution of 3-acetoxy-1-
(4-methoxybenzyl)-2,5-pyrrolidinedione (1a, 12.7 g, 46.0 mmol) in ethanol
(460 ml), and the solution was stirred at 508C for 3.5 h. After removal of
the solvent, the residue was dissolved in a solution of TBDMS-Cl (9.63 g,
64.5 mmol) and imidazole (5.88 g, 86.4 mmol) in DMF (150 ml) and the
mixture was stirred at room temperature for 19 h. After removal of the
solvent, the residue was extracted with ethyl acetate and the organic layer
was washed with water, dried over MgSO4, and evaporated in vacuo. The
residue was chromatographed on silica gel. Elution with a mixture of
hexane and ethyl acetate (70 : 30) gave the title compound 1b (15.3 g, 55%).
1H NMR (CDCl3) d 0.15 (s, 3H), 0.17 (s, 3H), 0.90 (s, 9H), 2.58
(dd, J ¼ 18 and 5 Hz, 1H), 2.98 (dd, J ¼ 18 and 8 Hz, 1H), 3.78 (s, 3H),
4.55 (dd, J ¼ 8 and 5 Hz, 1H), 4.56 (d, J ¼ 14 Hz, 1H), 4.62 (d, J ¼ 14 Hz,
1 H), 6.83 (d, J ¼ 9 Hz, 2H), 7.33 (d, J ¼ 9 Hz, 2H). 13C NMR (CDCl3)
d 25.3, 24.7, 18.2, 25.6, 38.8, 41.7, 55.2, 67.9, 113.9, 127.9, 130.4, 159.3,
173.9, 176.3. HRMS m/z 350.1799 [(M þ H)þ, calcd. for C18H28NO4Si
350.1788].
5-Acetoxy-4-tert-butyldimethylsiloxy-1-(4-methoxybenzyl)-2-pyrrolidinone
(2b). NaBH4 (1.04 g, 27.6 mmol) was added to a solution of 1b (1.61 g,
4.60 mmol) in methanol (35 ml) at 08C and the mixture was stirred for 1 h.
Then, saturated aqueous NaHCO3 (50 ml) was added to the reaction mixture
and methanol was evaporated in vacuo. The residue was extracted with
chloroform and the organic layer was dried over MgSO4. After removal of
the solvent, the residue was treated with acetic anhydride (2.59 g,
25.4 mmol) in pyridine (30 ml) at room temperature for 14 h and concentrated
in vacuo. The residue was extracted with ethyl acetate, and the organic layer
was washed successively with 1 M HCl and saturated aqueous NaHCO3, dried
over MgSO4, and evaporated. Chromatography (hexane : ethyl acetate ¼
50 : 50) of the crude product gave the title compound 2b (1.32 g, 73%) as a
76 : 24 mixture of inseparable diastereomers.
4-tert-Butyldimethylsiloxy-5-cyano-1-(4-methoxybenzyl)-2-pyrrolidinone
(3b). A solution of boron trifluoride diethyl etherate (950 mg, 6.68 mmol) in
dichloromethane (3 ml) was added to a solution of 2b (1.32 g, 3.34 mmol) and

3-Hydroxyglutamic Acid Synthesis
2965
trimethylsilyl cyanide (520 mg, 5.01 mmol) in dichloromethane (17 ml) at 08C
under an argon atmosphere, and the mixture was stirred for 1 h. Then,
saturated aqueous NaHCO3 (45 ml) was added to the reaction mixture, and
it was extracted with ethyl acetate. The organic layer was dried over
MgSO4, concentrated, and chromatographed on silica gel. Elution with a
mixture of hexane : ethyl acetate (60 : 40) afforded cis-3b (680 mg, 56%) as
1
an oil. H NMR (CDCl3) d 0.09 (s, 3H), 0.10 (s, 3H), 0.91 (s, 9H), 2.55
(dd, J ¼ 15 and 8 Hz, 1H), 2.67 (dd, J ¼ 15 and 8 Hz, 1H), 3.80 (s, 3H),
3.92 (d, J ¼ 15 Hz, 1H), 4.22 (d, J ¼ 6 Hz, 1H), 4.47 (ddd, J ¼ 8, 8, and
6 Hz, 1H), 5.14 (d, J ¼ 15 Hz, 1H), 6.88 (d, J ¼ 9 Hz, 2H), 7.20
(d, J ¼ 9 Hz, 2H). 13C NMR (CDCl3) d 25.0, 24.8, 17.9, 25.5, 39.5, 44.6,
55.0, 55.3, 65.5, 114.3, 114.4, 126.5, 130.0, 159.6, 171.0. HRMS m/z
360.1893 (Mþ, calcd. for C19H28N2O3Si 360.1869).
Further elution with a mixture of hexane : ethyl acetate (50 : 50) afforded
1
trans-3b (500 mg, 42%) as an oil. H NMR (CDCl3) d 0.02 (s, 3H), 0.05
(s, 3H), 0.81 (s, 9H), 2.42 (dd, J ¼ 17 and 3 Hz, 1H), 2.84 (dd, J ¼ 17 and
7 Hz, 1H), 3.80 (s, 3H), 3.88 (d, J ¼ 2 Hz, 1H), 3.91 (d, J ¼ 15 Hz, 1H),
4.60 (ddd, J ¼ 7, 3, and 2 Hz, 1H), 5.16 (d, J ¼ 15 Hz, 1H), 6.85
(d, J ¼ 9 Hz, 2H), 7.18 (d, J ¼ 9 Hz, 2H). 13C NMR (CDCl3) d 25.1,
25.0, 17.7, 25.4, 40.0, 44.3, 55.3, 56.0, 69.4, 114.4, 115.7, 126.2, 129.6,
159.6, 171.5. HRMS m/z 360.1913 (Mþ, calcd. for C19H28N2O3Si 360.1869).
(2R,3S)- and (2S,3S)-3-Hydroxyglutamic Acid (4). A solution of CAN
(4.12 g, 7.52 mmol) in water (8 ml) was added to a solution of cis-3b
(680 mg, 1.88 mmol) in acetonitrile (14 ml) at 08C, and the mixture was
stirred for 5 h. The reaction mixture was partitioned between ethyl acetate
(100 ml) and water (50 ml), and the organic layer was washed with
saturated aqueous NaHCO3 and concentrated in vacuo. The crude product
was directly hydrolyzed in refluxing 6 M HCl (20 ml) for 15 h. The cooled
aqueous solution was washed with chloroform and concentrated to dryness.
The residue was submitted to ion-exchange column chromatography on
Dowex 50W-X8 and elution with 1 M NH4OH gave the title compound
1
(2R,3S)-4 (130 mg, 43%) as the ammonium salt. H NMR (D2O) d 2.33 (dd,
J ¼ 16 and 9 Hz, 1H), 2.44 (dd, J ¼ 16 and 5 Hz, 1H), 3.55 (d, J ¼ 4 Hz,
1H), 4.31 (ddd, J ¼ 9, 5, and 4 Hz, 1H).
Similar treatment of trans-3b (450 mg, 1.26 mmol) afforded (2S,3S)-4 (80 mg,
40%). 1H NMR (D2O) d 2.27 (m, 2H), 3.68 (d, J ¼ 4 Hz, 1H), 4.28 (m, 1H).
REFERENCES
1. (a) Shimamoto, K.; Ishida, M.; Shinozaki, H.; Ohfune, Y. J. Org. Chem. 1991, 56,
4167–4176; (b) Shimamoto, K.; Ohfune, Y. J. Med. Chem. 1996, 39, 407–423;
(c) Dinsmore, A.; Doyle, P. M.; Young, D. W. Tetrahedron Lett. 1995, 36,
7503–7506; (d) Conti, P.; Dallanoce, C.; Amici, M. D.; Micheli, C. D.;

2966
M. Oba et al.
Fruttero, R. Tetrahedron 1999, 55, 5623–5634; (e) Kozikowski, A. P.;
Steensma, D.; Araldi, G. L.; Tu¨ckmantel, W.; Wang, S.; Pshenichkin, S.;
Surina, E.; Wroblewski, J. T. J. Med. Chem. 1998, 41, 1641–1650; (f) Gu, Z.-Q.;
Hesson, D. P.; Pelletier, J. C.; Maccecchini, M.-L. J. Med. Chem. 1995, 38,
2518–2520.
2. (a) Oba, M.; Koguchi, S.; Nishiyama, K. Tetrahedron Lett. 2001, 42, 5901–5902;
(b) Oba, M.; Koguchi, S.; Nishiyama, K. Tetrahedron 2002, 58, 9359–9363;
(c) Oba, M.; Koguchi, S.; Nishiyama, K. Tetrahedron 2004, 60, 8089–8092.
3. (a) Zhang, W.; Takeuchi, H.; Kurono, M. Gen. Pharmacology 1996, 27, 499–504;
(b) Watanabe, K.; Takeuchi, H.; Kurono, M. Eur. J. Pharmacol. 1985, 111, 57–63.
4. (a) Vidal-Cros, A.; Gaudry, M.; Marquet, A. J. Org. Chem. 1985, 50, 3163–3167;
(b) Kamiya, T. Chem. Pharm. Bull. 1966, 14, 1307–1309.
5. Shoji, J.; Salazaki, R. J. Antibiot. 1970, 23, 418–419.
6. (a) Veeresa, G.; Datta, A. Tetrahedron Lett. 1998, 39, 3069–3070;
(b) Dell’Uomo, N.; Giovanni, M. C. D.; Misiti, D.; Zappia, G.; Monache, G. D.
Liebigs Ann. Chem. 1994, 641–644; (c) Blaskovich, M. A.; Lajoie, G. A. J. Am.
Chem. Soc. 1993, 115, 5021–5030; (d) Shiokawa, S.; Ohta, T.; Nozoe, S. Chem.
Pharm. Bull. 1992, 40, 1398–1399; (e) Roemmele, R. C.; Rapoport, H. J. Org.
Chem. 1989, 54, 1866–1875; (f) Takahata, H.; Takamatsu, T.; Yamazaki, T.
J. Org. Chem. 1989, 54, 4812–4822; (g) Kunieda, T.; Ishizuka, T.; Higuchi, T.;
Hirobe, M. J. Org. Chem. 1988, 53, 3381–3383; (h) Garner, P. Tetrahedron Lett.
1984, 25, 5855–5858.
7. Louwrier, S.; Ostendorf, M.; Boom, A.; Hiemstra, H.; Speckamp, W. N.
Tetrahedron 1996, 52, 2603–2628.
8. Thaning, M.; Wistrand, L.-G. Acta Chem. Scand. 1989, 43, 290–295.