A concise diastereoselective synthesis of (2S,3S,4R)-3,4-dihydroxyglutamic acid

Article abstract of DOI:10.1016/S0040-4039(01)01120-0

A concise diastereoselective synthesis of (2S,3S,4R)-3,4-dihydroxyglutamic acid, one of eight possible stereoisomers of 3,4-dihydroxyglutamic acids, is described. The key reaction in this synthesis is stereoselective cyanation of an optically active N-acyliminium intermediate derived from L-tartaric acid with tributyltin cyanide.

Full text of DOI:10.1016/S0040-4039(01)01120-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5901–5902
A concise diastereoselective synthesis of
(2S,3S,4R)-3,4-dihydroxyglutamic acid
Makoto Oba,* Shinichi Koguchi and Kozaburo Nishiyama*
Department of Material Science and Technology, Tokai University, 317 Nishino, Numazu, Shizuoka 410-0395, Japan
Received 29 May 2001; revised 20 June 2001; accepted 25 June 2001
Abstract—A concise diastereoselective synthesis of (2S,3S,4R)-3,4-dihydroxyglutamic acid, one of eight possible stereoisomers of
3,4-dihydroxyglutamic acids, is described. The key reaction in this synthesis is stereoselective cyanation of an optically active
N-acyliminium intermediate derived from L-tartaric acid with tributyltin cyanide. © 2001 Elsevier Science Ltd. All rights reserved.
In the mammalian central nervous system,
L
-glutamic
Hydroxylated glutamic acid derivatives are considered
to be potent candidates for such subtype-selective lig-
ands based on their additional ability of intra- and
intermolecular hydrogen bonding. Although some
methods for the preparation of 3- and 4-hydroxyglu-
tamic acids have appeared in the literature,2 the corre-
sponding 3,4-dihydroxy derivatives have been less
studied. Since the first isolation of the 3,4-dihydroxy-
glutamic acid from the seeds of Lepidum sativum and the
leaves of Rheum rhaponticum,3 this acidic amino acid
was often found in several plants; however, the relative
and absolute configurations of the three chiral centers
acid acts as an excitatory neurotransmitter through the
ionotropic and metabotropic glutamate receptors. The
glutamate receptors can be subdivided into three
(NMDA, AMPA, and KA receptors) and eight sub-
types (mGluR1–8), respectively. The development of
subtype-specific agonists for glutamate receptors is
indispensable for therapeutic purpose as well as investi-
gating the physiological role of the receptors because of
the implication of the receptors in brain ischemia,
epilepsy and neurodegenerative syndromes such as
Alzheimer’s, Parkinson’s and Huntington’s diseases.1
TBSO
OTBS
TBSO
OTBS
TBSO
OTBS
a, b
c
L-tartaric acid
O
O
O
OAc
O
N
N
N
PMB
PMB
PMB
1
2
3
TBSO
OTBS
TBSO
OTBS
OH
e, f
d
HO2C
CO2H
+
O
CN
O
CN
N
N
OH
5b
NH2
PMB
PMB
(10 : 90)
4a
4b
OH
e, f
HO2C
CO2H
OH
NH2
5a
Scheme 1. (a) NaBH4, 97%; (b) Ac2O, pyridine, 85%; (c) BF3–OEt2; (d) Bu3SnCN, 94%; (e) Ce(NH4)2(NO2)6; (f) 6 M HCl, 110°C,
then Dowex 50W-X8, 54 and 73% yields for 5a and 5b, respectively (two steps).
* Corresponding authors. Tel.: +81-559-68-1111; fax: +81-559-68-1155; e-mail: makoto@wing.ncc.u-tokai.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01120-0

5902
M. Oba et al. / Tetrahedron Letters 42 (2001) 5901–5902
were unknown. Recently, two groups reported the
stereoselective synthesis of (2S,3S,4S)- and (2S,3S,4R)-
3,4-dihydroxyglutamic acids,4 and the former compound
was found to be a selective agonist of mGluR1.5 However,
the methods are extremely tedious and lack applicability
to other diastereomers. Therefore, a simple and general
synthetic method of all diastereomers must be designed.
We here disclose a concise diastereoselective synthesis of
(2S,3S,4R)-3,4-dihydroxyglutamic acid. In this synthesis
conversion of the minor isomer 4a was also carried out
and the diastereomeric (2R,3S,4R)-3,4-dihydroxyglu-
tamic acid (5a),13 a novel glutamic acid derivative, was
obtained in 54% yield.
In summary, we have demonstrated the concise
diastereoselective synthesis of (2S,3S,4R)-3,4-dihydroxy-
glutamic acid (5b) based on the stereoselective cyanation
of the chiral N-acyliminium ion 3 derived from L-tartaric
(Scheme 1), we adopted
L
-tartaric acid as the starting
acid. In this synthesis, the (2R,3S,4R)-isomer 5a was also
material because the acid already contains the required
obtained as a concomitant product. Although we have
two hydroxyl groups with established configurations.
not employed D-tartaric acid as a starting material, we
can see no reason why such reactions should not proceed
with equally high diastereoselectivity to afford the corre-
sponding (3R,4S)-isomers. The application of the present
protocol to the synthesis of the (3S,4S)- and (3R,4R)-
series of 3,4-dihydroxyglutamic acids is now under inves-
tigation.
The chiral imide 16 derived from
L-tartaric acid was
reduced with sodium borohydride into hydroxylactam in
97% yield, which was then converted to acetoxylactam
2 in 85% yield. The hydroxylactam itself and the corre-
sponding methoxylactam were inactive toward the subse-
quent cyanation reaction. The acetoxylactam 2 was then
subjected to various cyanation conditions and the results
are compiled in Table 1. When a solution of the lactam
2 (2.62 g, 5.00 mmol) and tributyltin cyanide7 (2.37 g, 7.50
mmol) in toluene (20 ml) was treated with trifluoroborane
etherate (1.42 g, 10.0 mmol) in toluene (5 ml), the expected
cyanolactam 48 was obtained in 94% yield as a 10/90
mixture of diastereomers (run 4). The choice of tributyltin
cyanide over the silicon reagent and toluene over
dichloromethane as the solvent proved to be advanta-
geous for the selective cyanation. No significant improve-
ment in the stereoselectivity was observed when the Lewis
acid was changed, and lower temperature greatly retarded
the reaction.
References
1. Conn, P. J.; Pin, J. P. Annu. Rev. Pharmacol. Toxicol. 1997,
37, 205–237.
2. (a) Dell’Uomo, N.; Di Giovanni, M. C.; Misiti, D.; Zappia,
G.; Delle Monache, G. Liebigs Ann. Chem. 1994, 641–644;
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ences cited therein.
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107–108.
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7. The enantioselective Strecker reaction of aldimine with
tributyltin cyanide was reported: Ishitani, H.; Komiyama,
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8. A closely related compound was prepared by a different
method: Kim, Y. J.; Kitahara, T. Tetrahedron Lett. 1997,
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9. (a) Yoda, H.; Kitayama, H.; Yamada, W.; Katagiri, T.;
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43, 290–295.
The stereochemistry of the newly created stereogenic
center of 4a and 4b was assigned according to the observed
vicinal coupling constants J4,5=4.4 and 6.7 Hz, respec-
tively.9 There are some reports on the Lewis acid-pro-
moted addition of tin and silicon nucleophiles to the
N-acyliminium ion syn to the adjacent OTBS group,9,10
revealing that this stereochemical outcome may be ruled
by the Cieplak-type stereoelectronic effect.11
The diastereomers 4a and 4b could be easily separated
by flash column chromatography on silica gel and the
cyanolactam 4a and 4b were independently transformed
into the 3,4-dihydroxyglutamic acids. The major isomer
4b was then treated with cerium ammonium nitrate
followed by 6 M HCl at 110°C. The crude product was
purified by ion exchange column chromatography
(Dowex 50W-X8) to furnish (2S,3S,4R)-3,4-dihydroxy-
glutamic acid (5b)12 in 73% yield based on 4b. The
10. (a) Schuch, C. M.; Pilli, R. A. Tetrahedron: Asymmetry
2000, 11, 753–764; (b) Ryu, Y.; Kim, G. J. Org. Chem.
1995, 60, 103–108; (c) Bernardi, A.; Micheli, F.; Potenza,
D.; Scolastico, C.; Villa, R. Tetrahedron Lett. 1990, 31,
4949–4952.
11. Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540–4552.
12. 1H NMR (D2O) l 3.96 (d, J=3 Hz, 1H), 4.24 (d, J=2 Hz,
1H), 4.51 (dd, J=3 and 2 Hz, 1H); 13C NMR (D2O) l 60.9,
72.4, 77.6, 175.4, 180.4; MS (FAB) m/z 180 (MH+).
13. 1H NMR (D2O) l 4.05 (d, J=5 Hz, 1H), 4.14 (d, J=2 Hz,
1H), 4.54 (dd, J=5 and 2 Hz, 1H); 13C NMR (D2O) l 61.9,
71.4, 76.2, 174.5, 180.4; MS (FAB) m/z 180 (MH+).
Table 1. Stereoselective cyanation of optically active acetoxy-
lactam 2
Run Metal cyanide Solvent
Selectivity
Yield (%)
(4a/4b)a
1
2
3
4
Me3SiCN
Me3SiCN
Bu3SnCN
Bu3SnCN
CH2Cl2
Toluene
CH2Cl2
Toluene
20/80
16/84
11/89
10/90
94
96
98
94
a Determined by 1H NMR spectroscopy.