Assymetric synthesis of (2S,3R)- and (2S,3S)-[2-13C;3-2H] glutamic acid

Article abstract of DOI:10.1016/j.tetlet.2009.01.062

We have developed a synthetic route for (2S,3R)- and (2S,3S)-[2-¹³C;3-²H] glutamic acids with high enantioselectivity. The key reactions in this synthesis are the asymmetric reduction of the 2,3-didehydroornithine derivative using th

Full text of DOI:10.1016/j.tetlet.2009.01.062

Tetrahedron Letters 50 (2009) 1482–1484
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Assymetric synthesis of (2S,3R)- and (2S,3S)-[2-13C;3-2H] glutamic acid
Kosuke Okuma a,b, Akira M. Ono a, Seiji Tsuchiya a, Makoto Oba b, Kozaburo Nishiyama b,
Masatsune Kainosho c,d, Tsutomu Terauchi a,
*
a SAIL Technologies Inc., 1-1-40, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan
b Department of Materials Chemistry, Tokai University, 317 Nishino, Numazu, Shizuoka 410-0395, Japan
c Graduate School of Science, Structural Biology Research Center, Nagoya University, Furo-cho, Chikusa-ku 464-8601, Japan
d Graduate School of Science, Tokyo Metropolitan University, 1-1 Minami-osawa, Hachioji, Tokyo 192-0397, Japan
a r t i c l e i n f o
a b s t r a c t
We have developed a synthetic route for (2S,3R)- and (2S,3S)-[2-13C;3-2H] glutamic acids with high
enantioselectivity. The key reactions in this synthesis are the asymmetric reduction of the 2,3-didehydro-
ornithine derivative using the (S,S)-Et-DuPHOS-Rh catalyst and the oxidation of the d-position by ruthe-
nium catalysis.
Article history:
Received 12 December 2008
Accepted 13 January 2009
Available online 19 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The replacement of 1H by 2H has been recognized as an efficient
method for eliminating undesired peaks in 1H nuclear magnetic
resonance (NMR) spectra and for observing NMR signals against
the relaxation caused by 1H.1 We recently proposed a novel label-
ing strategy, termed stereo-array isotope labeling (SAIL), for high-
throughput NMR structure determination of proteins.2 In the case
of amino acid metabolism studies, the analysis of 13C isotope shifts
induced by H/2H exchange in a 2H2O system is utilized.3 In this
study, we carried out the chemical synthesis of (2S,3S)- and
(2S,3R)-[2-13C;3-2H] glutamic acids for metabolic analysis. Several
groups have reported the stereoselective synthesis of glutamic acid
derivatives labeled with deuterium at prochiral protons.4 However,
these synthetic routes were not suitable for regioselective 13C
labeling coupled with deuterium labeling because the starting
13C-labeled materials were unavailable. We therefore wish to
report the simple synthesis of (2S,3S)- and (2S,3R)-[2-13C;3-2H]
glutamic acids via the asymmetric hydrogenation of a 2,3-didehyd-
roamino acid derivative, prepared from commercially available
materials. Generally, during the synthesis of glutamic acid labeled
with deuterium at the b-position, the synthetic route involving the
hydrogenation of the 2,3-didehydroglutamic acid derivative may
be straightforward. To the best of our knowledge, the regioselec-
tive 13C labeling of the 2,3-didehydroglutamic acid derivative can
derivative into the target [2-13C; 3-2H] glutamic acids by oxidation
of the d-position.
As shown in Scheme 1, the synthesis of (2S,3R)-[2-13C;3-2H]
glutamic acid (7) commenced with the preparation of the
stable isotope-labeled dehydroornithine derivative (3) using the
Horner–Wadsworth–Emmons6 reaction. The starting N-Boc-3-
amino[1-2H]propionaldehyde (1) was prepared by the reduction
of the Weinreb amide7 of N-Boc-b-alanine with lithium aluminum
deuteride (LiAlD4),8 and was then condensed with phos-
phoryl[2-13C]glycine ester (2)9 in the presence of 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU) to give 2,3-didehydro[2-13C;3-2H]-
ornithine (3) in 71% yield. Highly Z-selective olefination was
observed when the reaction was conducted at À25 °C.
Asymmetric hydrogenation of the obtained dehydroornithine
(3) was carried out under medium pressure (0.4 MPa) of hydrogen
in the presence of (+)-1,2-bis[(2S,5S)-2,5-diethylphospholano]ben-
zene (cyclooctadiene)rhodium(I) trifluoromethanesulfonate [(S,S)-
Et-DuPHOS-Rh], because the DuPHOS family of catalysts is highly
efficient for the hydrogenation of b-monosubstituted acetamidoac-
rylates, yielding a variety of amino acids with high enantioselectiv-
ities.10 In our previous study, a DuPHOS-Rh catalyst was also
employed for the asymmetric hydrogenation of dehydroserine
derivatives.11 The stereochemistry at the
a- and b-positions of
be achieved by using an
a
-oxoglutarate or a dehydroserine deriva-
[2-13C;3-2H]ornithine (4) was determined after the final glutamic
acid was obtained.
tive as the starting material. This report describes a simple method
for the synthesis of [2-13C;3-2H] glutamic acid, routed through
ornithine as the key intermediate. Asymmetric hydrogenation of
the [2-13C;3-2H] 2,3-didehydroornithine derivative,5 which is de-
rived from readily available [2-13C] glycine and b-alanine, is carried
out to yield an ornithine derivative labeled with deuterium at the
b-position. This is stereoselectively followed by conversion of the
According to Yoshifuji’s procedure,12 the conversion of
ornithine (4) to glutamine (5) was performed using a catalytic
amount of ruthenium dioxide and an excess of sodium periodate
in a two-phase system of ethyl acetate and water. However,
[2-13C;3-2H]glutamine (5) was obtained in only 38% yield because
of the considerable side reaction yielding the cyclic compound 6.
Hydrolysis of 5 was performed by refluxing it in 2 M HCl, and
subsequent ion exchange treatment of the obtained glutamic acid
hydrochloride with DOWEX 50WX8 afforded (2S,3R)-[2-13C;3-2H]
* Corresponding author. Tel.: +81 45 508 7651; fax: +81 45 508 7652.
E-mail address: terauchi@sail-technologies.com (T. Terauchi).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.062

K. Okuma et al. / Tetrahedron Letters 50 (2009) 1482–1484
1483
Scheme 1. Reagents and conditions: (i) DBU, CH2Cl2, À25 °C, 71%; (ii) (S,S)-Et-DuPHOS-Rh, benzene, H2 (0.4 MPa), 84%; (iii) RuO2, NaIO4, ethyl acetate-H2O, 38%; (iv) 2 M HCl
reflux; (v) DOWEX 50WX8, 70% (2 steps).
glutamic acid (7) in 70% yield. The enantiopurity based on the
a
-
The (S,S)-Et-DuPHOS-Rh catalyst afforded [2-13C;2,3-2H2]ornithine
(10) in 98% yield with the (2S,3S)-configuration, which was con-
firmed after its conversion to glutamic acid.
The obtained ornithine (10) was then subjected to ruthenium-
catalyzed oxidation. Sheldon and co-workers pointed out that
low pH has a detrimental effect on a catalytic system involving
ruthenium tetroxide.13 We found that keeping the pH mildly alka-
line by adding aqueous sodium carbonate during the course of the
reaction improved the chemical yield of the glutamine from 38%
(for 5) to 64% (for 11).
position was determined to be 99% ee by high performance liquid
chromatography (HPLC) analysis using a chiral column (MCIGEL
CRS10W). Figure 1a shows the 300 MHz1H NMR spectrum of 7.
As compared to that of the unlabeled glutamic acid (Fig. 1d), the
signal for the 3R proton disappears completely, indicating that 7
has R stereochemistry at the b-position. This stereochemical out-
come can be attributed to the exclusive cis-addition of hydrogen
to the a-re-face of deuterated (Z)-2,3-didehydroornithine (3), pro-
moted by the (S,S)-Et-DuPHOS-Rh catalyst.
We next performed the asymmetric deuteration of 2,3-didehy-
dro[2-13C]ornithine (9), prepared from N-Boc-3-aminopropional-
dehyde (8) and 2, in 60% yield (Scheme 2), in order to obtain its
isotopic stereoisomer, (2S,3S)-[2-13C;3-2H] glutamic acid (13).
The glutamine (11) was then deprotected to give (2S,3S)-
[2-13C;2,3-2H2] glutamic acid (12) in 82% yield. The enantiopurity
of 12 with respect to the
a-position was also confirmed by HPLC
analysis to be 99% ee. Its 1H NMR spectrum (Fig. 1b) confirmed that
Figure 1. 300 MHz 1H NMR spectra of (a) (2S,3R)-[2-13C;3-2H]glutamic acid (7), (b) (2S,3S)-[2-13C;2,3-2H2]glutamic acid (12), (c) (2S,3S)-[2-13C;3-2H]glutamic acid (13), and
(d) unlabeled glutamic acid in NaOD–D2O.

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K. Okuma et al. / Tetrahedron Letters 50 (2009) 1482–1484
Scheme 2. Reagents and conditions: (i) 2, DBU, CH2Cl2, À25 °C, 83%; (ii) (S,S)-Et-DuPHOS-Rh, benzene, D2 (0.4 MPa), 98%; (iii) RuO2, NaIO4, Na2CO3, ethyl acetate–H2O, 64%;
(iv) 2 M HCl reflux; (v) DOWEX 50WX8, 82% (2 steps); (vi) 5 M NaOH, (CH3CO)2O, 38 °C; (vii) porcine kidney acylase I, pH 8, 37 °C; (viii) DOWEX 50WX8, (13): 39% (2 steps),
(14):43%.
the regioselective and stereoselective incorporation of stable
isotopes were accomplished. Finally, we carried out deuterium-
hydrogen exchange at the a-position using a traditional racemiza-
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In summary, we have achieved the asymmetric synthesis of
(2S,3R)- and (2S,3S)-[2-13C;3-2H] glutamic acids with high enanti-
oselectivity. The key reactions in this synthesis are the asymmetric
hydrogenation or deuteration of the 2,3-didehydroornithine deriv-
ative using the (S,S)-Et-DuPHOS-Rh catalyst and the subsequent
ruthenium-catalyzed d-oxidation leading to the formation of the
glutamine derivative. Further modification of the present proce-
dure to obtain other labeled amino acids is now underway.
Acknowledgments
We are grateful to A. Shirai for mass spectrum analyses. This
work has been supported by the Core Research for Evolutional Sci-
ence and Technology (CREST) of the Japan Science and Technology
Agency (JST).
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