Synthesis of isotope-labelled [1-13C]-amino acids from 13CO2

Full text of DOI:10.1002/jlcr.1379

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 622–623.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1379
Short Research Article
y
Synthesis of isotope-labelled [1-13C]-amino acids from 13CO2
TAKAYUKI NAKAJIMA, KAZUKI NAKAYAMA and ISAO SHIMIZU*
Department of Applied Chemistry, School of Science and Engineering, Waseda University, Ohkubo 3-4-1, Shinjuku-ku, Tokyo 169-8555, Japan
Received 8 July 2006; Revised 2 March 2007; Accepted 30 March 2007
Keywords: isotope-labelled [1-13C]-amino acids; 13CO2; asymmetric hydrogenation
Introduction
followed by hydroxylation gave [1-13C]-nitroacetic acid
in 58% yield, which was subjected to hydrogenation
with H2 on Pd/C to afford [1-13C]-glycine in 68% yield.
(Scheme 1)
Much attention has been paid to the application of stable
isotope-labelled 13C-amino acids to various biological
studies, such as metabolism, the diagnosis of disease,
and biosynthetic studies and the structural analysis of
peptides and proteins, because 13C atom is analyzed in
multiple ways as IR, NMR and mass spectroscopy.1 We
present here a convenient method for preparation of
[1-13C]-amino acids by fixation of readily available 13CO2
by means of methyl magnesium carbonate (MMC).
Synthesis of optically active amino acids from
[1-13C]-glycine was also studied. Thus, [1-13C]-glycine
was converted into 2-(methoxyphosphono)glycine
derivative,3 which was subjected to the Horner–
Wadsworth–Emmons reaction with several aldehydes
to afford corresponding dehydroamino acid deriva-
tives with high Z selectivity4 (Scheme 2). Rhodium
catalyzed-asymmetric
hydrogenation
of
dehyd-
roamino acids gave [1-13C]-amino acids with high ee
(Table 1).5
Results and discussion
13C-MMC was prepared from Mg(OMe)2 and 13CO2
in DMSO.2 The reaction of nitromethane and 13C-MMC,
13CO2H
13CO2H
1) MeOMgO13CO2Me
MeNO2
Pd/C, H2(1 atm)
AcOH
2) conc.HCl
NO2
58% (2 steps)
NH2
68%
Scheme 1
*Correspondence to: Isao Shimizu, Department of Applied Chemistry,
School of Science and Engineering, Waseda University, Ohkubo 3-4-1,
Shinjuku-ku, Tokyo 169-8555, Japan. E-mail: shimizui@waseda.jp
yProceedings of the Ninth International Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
16–20 July 2006.
Copyright # 2007 John Wiley & Sons, Ltd.

SYNTHESIS OF ISOTOPE-LABELLED [1-13C]-AMINO ACIDS 623
13CO2H
NH2
13CO2Me
13CO2Me
Br
P(OMe)3
NBS, h
ν
1. SOCl2,MeOH
2. (Boc)2O, Et3N
CH2Cl2, reflux
CCl2
NHBoc
NHBoc
93% (2 steps)
O
13CO2Me
13CO2Me
RCHO
Rh-L*
H2
13CO2Me
MeO P
MeO
R
R
NHBoc
NHBoc
NHBoc
90%(2 steps)
Scheme 2
Table 1 Asymmetric hydrogenation of dehydroamino acids
H
H
[(S,S)-Et-DuPHOS-Rh(COD)] +OTf–(1 mol%)
H2 (5.0 atm), MeOH, 50 °C
13CO2Me
13CO2Me
R
R
NHBoc
NHBoc
Entry
1
R
Time (h)
22
Yield (%)
99
ee (%)
92
2
3
4
16
22
26
22
98
99
98
99
94
94
96
93
MeO
N
Boc
H
5
6
7
8
BnO
19
19
18
98
97
99
94
93
92
O
BocHN
Boc2N
O
REFERENCES
2. Finkbeiner HM, Stiles M. J Am Chem Soc 1963; 85:
616.
1. (a) Mason AJ, Siarheyeva A, Haase W, Lorch M, Veen
¨
H, Glaubitz C. FEBS Lett 2004; 568: 117; (b) Lohr F,
3. Kober R, Steglich W. Liebigs Ann Chem 1983; 599.
4. Schmidt U, Griesser H, Leitenberger V, Lieberknecht
A, Mangold R, Meyer R, Riedl B. Synthesis 1992;
487.
5. Burk MJ, Feaster JE, Nugent A, Harlow RL. J Am
Chem Soc 1993; 115: 10125.
¨
Rogov VV, Shi M, Bernhard F, Dotsch V.
Biomol NMR 2002; 23: 333; (c) Persson J,
J
¨
Nasholm T. Physiol Plant 2001; 113: 352; (d)
Torizawa T, Ono AM, Terauchi T, Kainosho M.
J Am Chem Soc 2005; 127: 12620.
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 622–623
DOI: 10.1002.jlcr