A concise synthesis of (2S,4R)- and (2S,4S)-4-methylglutamic acid

Article abstract of DOI:10.1016/S0040-4039(03)00429-5

A concise, multi-gram scale method for producing the bioactive and enantiomerically pure epimers, (2S,4R)- and (2S,4S)-glutamic acids, in a single synthetic scheme is described.

Full text of DOI:10.1016/S0040-4039(03)00429-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3203–3205
A concise synthesis of (2S,4R)- and (2S,4S)-4-methylglutamic
acid
Zi-Qiang Gua and Min Lib,*
aLaboratory of Medicinal Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA
bSunmack Science Inc, PO Box 7002, Gaithersburg, MD 20898, USA
Received 2 January 2003; revised 12 February 2003; accepted 13 February 2003
Abstract—A concise, multi-gram scale method for producing the bioactive and enantiomerically pure epimers, (2S,4R)- and
(2S,4S)-glutamic acids, in a single synthetic scheme is described. © 2003 Elsevier Science Ltd. All rights reserved.
Analogs of glutamic acid have been found to be useful
probes for studying a number of biological systems
including various enzymes1–3 and receptors.4–7 In partic-
(S)-pyroglutamic acid in methanol.14 The NH group of
the methyl or ethyl ester (2) was further protected with
the BOC group by using a standard procedure.15 In a
typical alkylation procedure, the fully protected pyro-
glutamate (3b, R=Et, 20 g scale) was enolized at the
4-position by using 1.03 equiv. LiN(SiMe3)2 in THF at
−78°C, and the enolate formed was then reacted with
2.5 equiv. methyl iodide. After workup, a mixture of
trans (4b), cis (5b), and disubstituted (6b) pyrogluta-
mate derivatives was obtained; separation of the mix-
ture was readily achieved on a silica gel column
chromatography to give 4b (7.8 g, 37% based on 3b), 5b
(6.0 g, 28%) and 6b (2.5 g, 11%), respectively.16 Each of
these compounds was subsequently deprotected via a
two-step procedure,13 in which the ester functionality
was taken off with an aqueous lithium hydroxide solu-
tion in THF and the BOC group removed by TFA in
methylene chloride. The (2S,4R)- and (2S,4S)-glutamic
acids (7 and 8, respectively) thus obtained displayed the
same spectroscopic properties as reported previ-
ously.11,13 The overall yield for the two isomers (7 and
8) combined was around 42% starting from compound
3b (similar yields were achieved by starting from the
methyl ester 3a).
ular, two isomers of 4-methyl-L-glutamic acid, i.e.
(2S,4R)- and (2S,4S)-4-methylglutamic acids (7 and 8,
Scheme 1), deserve special attention, as the (2S,4R)
isomer is a highly selective and potent agonist for
kainate receptors,5,6 while the (2S,4S) one is a potent
agonist for metabotropic receptors.7 The two isomers
may be prepared in enantiomerically pure forms by
procedures that have been reported in the literature,
which include asymmetric syntheses using enzymes8,9 or
chiral auxiliaries,10 and alkylation of protected
glutamates11 or pyroglutamates12 and related com-
pounds.13 One of the latter procedures, reported by
Coudert et al., produced the two isomers (63:37 molar
ratio) in a single reaction sequence, which was followed
by two steps of ion-exchange chromatography to yield
the two enantiomerically pure epimers.12 In this paper,
we report a simpler preparation of the two enantiomer-
ically pure epimers in a single reaction sequence which
involves less synthetic steps and requires only one silica
gel column chromatography.
The preparation (Scheme 1) can start from either one of
the commercially available starting materials, (S)-
pyroglutamic acid or its ethyl ester (both are available
from Fluka). In the former case, (S)-pyroglutamic acid
was converted to its methyl ester (1) by addition of
thionyl chloride into an ice-water cooled solution of
In summary, a concise method for preparing the bio-
logically active and enantiomerically pure epimers,
(2S,4R)- and (2S,4S)-4-methylglutamic acids, in a sin-
gle synthetic scheme has been described. It provides an
efficient and practical way of making the two isomers
or the corresponding diastereomers, (2R,4S)- and
(2R,4R)-4-methylglutamic acids, if the synthesis starts
with (R)-pyroglutamic acid. The overall procedure is
readily scaled up beyond the multi-gram level.
Keywords: 4-methylglutamic acid; synthesis; enantiomerically pure.
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00429-5

3204
Z.-Q. Gu, M. Li / Tetrahedron Letters 44 (2003) 3203–3205
Scheme 1.
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Z.-Q. Gu, M. Li / Tetrahedron Letters 44 (2003) 3203–3205
3205
using procedure described in Ref. 11. The drawback of
this approach, however, is that slight epimerization
occurred at the C-4 position.
mixture was continuously stirred at −78°C for another 2
h and then was allowed to gradually warm to room
temperature overnight under nitrogen. After the reaction
mixture was quenched with 2 equiv. acetic acid and 30
mL of water, it was concentrated in vacuo. The concen-
trated residue was diluted with water and then extracted
with ethyl acetate. The organic extracts were combined
and washed with water and brine, respectively. After the
washed solution was dried over anhydrous magnesium
sulfate, it was evaporated in vacuo to produce an oily
residue. The residue was loaded onto a silica gel column
and eluted with a mixture of ethyl acetate/hexane (1/2,
v/v). Eluted first was the 4,4-dimethyl compound (6b, 2.5
g, 11%). 1H NMR (200 MHz, CDCl3): l 4.50 (m, 1H),
4.20 (q, 2H, J=7.2 Hz), 2.19 (m, 1H), 1.88 (m, 1H), 1.47
(s, 9H), 1.40 (s, 3H), 1.34–1.14 (m, 6H). The trans-isomer
(4b) came out next (7.8 g, 37%). 1H NMR (CDCl3): l
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16. Detailed procedures for the alkylation: a solution of
compound 3b (20 g, 77.8 mmoL) in 200 mL of THF was
cooled to −78°C, followed by slow addition of 80 mL of
1.0 M LiN(SiMe3)2 solution in THF. After the addition,
the solution was stirred for 45 min and methyl iodide (12
mL, 195 mmoL) was added in one portion. The resulting