Asymmetric nitroaldol reaction using nitromethane labeled with 11C

Article abstract of DOI:10.1016/j.tetlet.2008.07.074

Nitro[¹¹C]methane produced from [¹¹C]O₂ reacted with several aldehydes in the presence of chiral metal catalyst prepared from LaLi₃{tris(binaphtoxide)}, n-BuLi, H₂O, and (R)-binaphtol. The molar ratio

Full text of DOI:10.1016/j.tetlet.2008.07.074

Tetrahedron Letters 49 (2008) 5837–5839
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Asymmetric nitroaldol reaction using nitromethane labeled with 11C
Koichi Kato a,b, , Sven Åke Gustavsson a,c, Bengt Långström a,c,
*
*
a Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, SE753 23 Uppsala, Sweden
b Department of Molecular Probes, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan
c Uppsala Imanet, GE Healthcare, Box 967, SE751 05 Uppsala, Sweden
a r t i c l e i n f o
a b s t r a c t
Nitro[11C]methane produced from [11C]O2 reacted with several aldehydes in the presence of chiral metal
catalyst prepared from LaLi3{tris(binaphtoxide)}, n-BuLi, H2O, and (R)-binaphtol. The molar ratios of La,
Li, and binaphtol for effective catalysis in the 11C-labeling were 1/4/4.5 and 1/4/6, respectively. The
11C-nitroaldol products were obtained in 3–25% radiochemical yields with 39–51% ee within 20 min
starting from the preparation of nitro[11C]methane.
Article history:
Received 22 February 2008
Revised 10 July 2008
Accepted 14 July 2008
Available online 17 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The positron-emitting radionuclide 11C (T1/2 = 20.3 min) which
is frequently used to prepare tracers and compounds labeled by
11C, can be utilized for in vivo imaging by positron emission
tomography (PET). PET has been recognized as a useful tool for
clinical diagnosis and the drug development process.1 Several con-
straints are limiting the development of new 11C-labeling methodo-
logy; rapid reaction under sub-micro molar scale, limited number
of labeling precursors, and a need for remote-controlled system
for radiation protection.2
Asymmetric labeling synthesis promoted by a chiral organome-
tallic catalyst offers a new prospect for 11C-labeling chemistry. The
methodology needs to be further explored, especially considering
the time constraints.3 The chiral center often plays an important
role in biological activity; therefore, asymmetric 11C-labeling syn-
thesis is sometimes required for precise PET analysis. Asymmetric
11C-labeling syntheses have been carried out by enzymatic synthe-
sis or using chiral handles;4,5 however, these methods require a
limited number of available substrates, resulting in no significant
impact on further development. The recent progress in asymmetric
catalysis by organometallics has shown exciting potential to solve
such problems.6 Although chemical and technical problems caused
by the use of short-lived radioisotopes complicate asymmetric
labeling synthesis, the use of an organometallic catalyst is attrac-
tive for 11C-labeling synthesis and should be considered for further
exploration.
oped by Shibasaki and co-workers, are binaphtol-modified La–Li
bimetallic catalysts that are effective in the asymmetric nitroaldol
reaction.8,9 Catalysts 2 and 3 may be useful because they are pre-
pared and used in the presence of water.8a Easy and reliable han-
dling of the catalyst is crucial to minimize technical problems
caused by the special conditions of radiolabeling, therefore, 2 and
3 were considered to be appropriate for 11C-labeling. In this Letter,
we describe asymmetric nitroaldol reactions using 1 in combina-
tion with the modification of 2 and 3 as a first attempt for use as
an asymmetric catalyst for 11C-labeling.
Including purification and formulation, the whole procedure
should be rapid, aiming at less than 1 h; therefore, the actual
11C-labeling is often terminated within 5 min in order to obtain a
high radiochemical yield, considering the competing decay both
of products and starting material.2 Thus in syntheses using short-
lived radionuclides, a higher reaction temperature is preferred in
order to speed up reaction rates and obtain a higher radiochemical
yield of the labeled product. The 11C-labeling reactions performed
in this paper proceeded at ꢀ10 °C and room temperature. Although
ꢀ50 °C was employed as a reaction temperature to obtain high ee
in Shibasaki’s reports, there was a compromise between ee and
radiochemical yield.
Cyclotron-produced [11C]O2 was immediately transformed into
[
11C]H3I via reduction by lithium aluminum hydride (LAH) and
subsequent iodination by hydroiodic acid (HI). [11C]H3I was then
We focused on the asymmetric nitroaldol reaction using
converted to 1 via nitration by passing through a heated column
[
11C]H3NO2 (1) as a model. Nitroaldol products can be transformed
to b-amino alcohols,7 which are structural elements of interesting
biological compounds with potential to become valuable PET trac-
ers. The asymmetric catalysts LLB (2) and LLB-II (3) (Fig. 1), devel-
*
*
Li
O
La
O
O
O
3
Li
*
*
Li
O
O
O
La
O
Li
OH
OH
=
O
O
O
O
LiOH
OH OH
*
*
*
Li
Li
2
* Corresponding authors. Tel.: +81 43 206 4042; fax: +81 206 3261 (K.K.); tel.:
+46 18 66 6900; fax: +46 18 18 0932 (B.L.).
E-mail addresses: katok@nirs.go.jp (K. Kato), Bengt.Langstrom@biorg.uu.se
(B. Långström).
4
Figure 1. Structures of 2, 3 and 4.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.074

5838
K. Kato et al. / Tetrahedron Letters 49 (2008) 5837–5839
Table 2
AgNO2
70 °C
1. LAH, rt
11CH3NO2
11CO2
11CH3I
O
OH
2. HI, 130 °C
1
B, THF
NO2
1
+
Ar 11C
Ar
H
−
10 °C, 5 min
Figure 2. Preparation of 1.
7a— c
8a— c
Entry
Ar
Product
Yielda,b
eeb (%)
containing silver nitrite and dried potassium carbonate (Fig. 2).10,11
Catalysts 2 and 3 with molar ratios of La, Li, and (R)-(+)-1,10-bi-
2-naphtol (4) of 1/3/3 and 1/4/3, respectively, were prepared in
accordance with the literature by using La(O-i-Pr)3, n-BuLi, and
4.8a The reaction between 1 and 3-phenylpropanal (5) was selected
to explore the feasibility of 11C-labeling by an asymmetric nitro-
aldol reaction because the ee value of the reaction between
CH3NO2 and 5 was high under the catalytic condition given in
the literature (73% ee).8b The initial labeling reaction was carried
out using 2. The radioactivity of 1 using studies was 0.2–2 GBq.
The mol amounts of 1 were uncertain, however, they could be esti-
mated at less than 100 nM.12 The reaction afforded 6 in approxi-
mately 50% ee, but radiochemical yield was less than 1% (Eq. 1).
1
2
3
C6H5 (7a)
p-NO2C6H4 (7b)
p-CH3C6H4 (7c)
8a
8b
8c
8
12
3
51
41
39
a
Yields were decay-corrected radiochemical conversion.
Determined by radio-HPLC.
b
the enantioselectivity of the 11C-labeling reaction obtained by A
and 2, catalyst A might not suppress the racemic reaction com-
pletely; therefore, the following catalyst solution was prepared
by adding 1.5 mol equiv of 4 to 3, forming a molar ratio of La, Li,
and 4 of 1/4/4.5 (catalyst B). The labeling reaction mediated by B
afforded 6 in 44% ee (entry 2) at ꢀ10 °C. Under 11C-labeling condi-
tions, B gave similar ee of the product as 2 and higher radiochem-
ical yield (9%).13,14 Stoichiometric reaction using cat B for CH3NO2
was carried out in the presence of 3 mol equiv of 5 at ꢀ10 °C. The
reaction gave non-labeled 6 in 69% yield and 39% ee for 20 h.15
When the 11C-labeling reaction mediated by B was carried out at
room temperature, the reaction afforded 6 in higher radiochemical
yield (29%), but in lower enantioselectivity (9% ee, entry 3). When
3 mol equiv of 4 was added to 3, a molar ratio of La, Li, and 4 of 1/4/
6 of the catalyst solution (catalyst C) was obtained. The 11C-label-
ing reaction mediated by C afforded 6 in similar enantioselectivity
O
OH
11C
NO2
2, THF
H
11CH3NO2
+
—10 °C, 5 min
1
5
6
>1% yield, ~50% ee
ð1Þ
When the same reaction was carried out using 3, the 11C-label-
ing reaction provided 6 in 50% radiochemical yield (Eq. 2); how-
ever, product 6 was racemic (Eq. 2). In the literature, catalyst 3
afforded nitroaldol products in similar enantioselectivity and high-
er reactivity than 2 under catalytic conditions;8a however, the 11C-
labeling reaction mediated by 3 yielded a racemic mixture.
(39%) and higher radiochemical yield (25%) as
temperature.
B at room
The reactions between 1 and benzaldehyde (7a) or other aro-
matic aldehydes 7b, 7c were also explored. In the literature, the
ee value of the reaction between CH3NO2 and 7a was moderate
(approximately 40% ee) under the catalytic condition using 2;16
however, 11C-labeled nitroaldol products derived from aromatic
aldehydes are interesting as PET tracers.7b All 11C-labeling reac-
tions were carried out by catalyst solution B at –10 °C. The 11C-
labeling reaction for 7a afforded 8a in 51% ee at ꢀ10 °C (Table 2,
entry 1). The ee value of 8a was higher than the reported ee value
of the catalytic condition at –40 °C even though a higher reaction
temperature was employed for 11C-labeling reaction. The molar
amount of 7a to 1 may play an important role in the ee value of
8a. Excess CH3NO2 to aldehyde was usually used under catalytic
conditions; however, a minute amount of 1 could be used under
the 11C-labeling conditions presented here. The undesired side
reaction might be suppressed in the reaction between 1 and 7a,
affording 8a in higher ee than the reaction performed under cata-
lytic conditions. The 11C-labeling reactions for 7b, 7c afforded 8b
and 8c in 41% ee and 39% ee, respectively. No significant difference
was observed for ee values of 8b and 8c (entries 2 and 3).
In summary, we investigated the asymmetric nitroaldol reac-
tion for 1 and several aldehydes. Enantioselective 11C-labeling
mediated by organometallic catalysts was performed and the ee
values of products were moderate but this is a first step to fuse
organometallic asymmetric catalysis and radiolabeling synthesis.
Recently, several environmentally friendly catalysts have been
developed, allowing reactions to be performed in the presence of
water,17 and some of these catalysts will further support the pro-
gress of radiolabeling chemistry and PET tracer development.
3, THF
−10 °C, 5 min
1
+
5
6
ð2Þ
50% yield
0% ee
LDI-TOF MS analysis of a solution of 2 suggested that the solu-
tion contained mixtures of complexes comprising several molar
ratios of Li, La, and 4.8c We considered that there was equilibrium
in the catalyst formation of 3, and free LiOH resulted from the equi-
librium at the higher reaction temperature employed for 11C-label-
ing conditions. The resulting free LiOH can mediate nitroaldol
reactions and cause problems with the racemic product. Thus,
the effect of a further addition of 4 to a solution of 3 was investi-
gated in order to force the equilibrium to form 3 with higher con-
centration and suppress the existence of free LiOH. Catalyst
solutions with three different ratios of Li, La, and 4 were used to
explore ee and the radiochemical yield of the reactions (Table 1).
First, 1 mol equiv of 4 was added to 3 to form a molar ratio of 1/
4/4 for Li, La, and 4 (catalyst A). In catalyst solution A, free LiOH
was assumed to be consumed. The labeling reaction mediated by
A afforded 6 in 15% ee at ꢀ10 °C (Table 1, entry 1). Compared to
Table 1
3 + 4
THF, 5 min
1 +
5
6
Entry
Cat. No.
4 (equiv)
La/Li/4
Temp (°C)
Yielda,b (%)
eeb (%)
1
2
3
4
A
B
B
C
1
1/4/4
ꢀ10
ꢀ10
rt
—
9
29
25
ꢁ15
44
9
1.5
1.5
3
1/4/4.5
1/4/4.5
1/4/6
Acknowledgment
rt
39
a
Yields were decay-corrected radiochemical conversion.
Determined by radio-HPLC.
This work was supported by a Postdoctoral Fellowship for
Research Abroad from JSPS (K.K.).
b

K. Kato et al. / Tetrahedron Letters 49 (2008) 5837–5839
5839
11. Gustavsson, S. Å.; Kato, K.; Långström, B. J. Labelled Compd. Radiopharm. 2003,
46, 1279–1285.
References and notes
12. The specific activity of 1 was not determined, but it could be considered to
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have similar value as [11C]H3I (around or higher than 37 GBq/
isotope contamination during nitration reaction.
lmol) due to no
13. Typical procedure of asymmetric nitroaldol reaction: [11C]Carbon dioxide was
produced by the 14N[p,
containing 0.05% oxygen bombarded with 17 MeV protons.
dioxide was reduced by 0.2 M LiAlH4 solution in THF (500 L), and thereafter
a]
11C nuclear reaction using a nitrogen gas target
[
11C]Carbon
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l
THF was evaporated. To the residue, a 54% HI aqueous solution (1 mL) was
added and the mixture was heated at 130 °C to give [11C]H3I in the gas phase. 1
was prepared by passing [11C]H3I through a column filled with silver nitrite at
70 °C and dried potassium carbonate. 1 was trapped in a 0.03 M catalyst
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solution in THF (300
L of the aldehyde was added. After 5 min, a saturated solution of aqueous
ammonium chloride (100 L) was added to quench the reaction mixture. The
lL). The reaction mixture was placed in a cooling bath and
5
l
l
contents of the vial were diluted and the formed product was purified by semi-
preparative HPLC.
14. Catalyst solution of B was prepared as below. To a solution of 4 (856 mg,
3 mmol) in THF (13 mL) a 1.6 M solution of n-BuLi (1.25 mL, 2 mmol) in
hexane was added at 0 °C. Soon a clear solution was changed to suspension,
then a 0.2 M solution of La(O-i-Pr)3 (2.5 mL, 0.5 mmol) in THF was added at
room temperature. After mixture was stirred overnight, water (9 lL, 0.5 mmol)
was added and the resulting catalyst solution was stored at room
temperature.
15. 1H NMR was measured for a mixture of 4 and non-labeled 6. Non-labeled 6 was
detected by GC and HPLC in the mixture. Yield was determined by HPLC using
methyl 4-chlorocinnamate as an internal standard. Ee was determined by HPLC
using CHIRALPAK AD-H (DAICEL).
16. Shibasaki et al. reported that using other lanthanide metal for catalysts gave
corresponding nitroaldol product in good ee for this reaction. Details are
described in Ref. 8d.
17. Li, C.-J. Chem. Rev. 2005, 105, 3095–3165.
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