No-carrier-added radiohalogenations utilizing organoboranes: The synthesis of iodine-123 labeled curcumin

Article abstract of DOI:10.1016/j.jorganchem.2008.11.040

The use of organoborane intermediates for radiohalogenations is briefly reviewed. The synthesis of an iodine-123 labeled curcumin derivative using a newly developed radio-iodination technique is reported.

Full text of DOI:10.1016/j.jorganchem.2008.11.040

Journal of Organometallic Chemistry 694 (2009) 1638–1641
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
No-carrier-added radiohalogenations utilizing organoboranes: The synthesis
of iodine-123 labeled curcumin
*
George W. Kabalka , Min-Liang Yao
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, TN 37996-1600, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 October 2008
Received in revised form 17 November 2008
Accepted 18 November 2008
Available online 30 November 2008
The use of organoborane intermediates for radiohalogenations is briefly reviewed. The synthesis of an
iodine-123 labeled curcumin derivative using a newly developed radio-iodination technique is reported.
Ó 2008 Elsevier B.V. All rights reserved.
Keywords:
Organoborane
Radiohalogenation
Curcumin
Organotrifluoroborate
Amyloid
1
. Introduction
The first report of isotope incorporation (tritium) via borane
priate alkenes were available. The preparation of aromatic borane
derivatives was even more problematic in that transmetallation
reactions were generally required. The necessity of using reactive
(and basic) Grignard and lithium reagents often precluded the
presence of interesting and useful functionality in the target
molecules.
intermediates appeared shortly after Brown’s initial report of the
hydroboration reaction [1,2]. The emphasis of the early tritiation
study was on reaction mechanisms and not on the synthesis of
radiolabeled organic molecules. What was clear in the 1960s was
that a large variety of functionally substituted organoborane deriv-
atives could be prepared and that they were well tolerated in sub-
sequent reactions in which the boron atom was replaced by other
elements and functional groups (Scheme 1). At that time, organo-
boranes were unique amongst the reactive organometallic and
organometalloidal reagents available because they could contain
a variety of functions groups while maintaining high reactivity [3].
The realization that one could prepare reactive intermediates
containing functional groups led us to investigate the use of
organoboranes in isotope-incorporation reactions. Over the years,
we successfully developed methods for incorporating short and
long lived isotopes of carbon, nitrogen, oxygen, and the halogens
The situation changed dramatically after Akira Suzuki and Norio
Miyaura discovered new palladium catalyzed carbon–carbon and
carbon–boron bond forming reaction; the new coupling reactions
generally occur at, or near, room temperature in the presence of
very mild organic and inorganic bases [6,7]. One only needs to
examine a current organic chemistry journal to realize the impact
of the palladium catalyzed, boron-based, Suzuki–Miyaura reac-
tions. Due to the importance of the Suzuki reaction, several novel
methods for preparing organoboron esters were developed in last
decade [8,9]. And these novel methods make it possible to readily
introduce a variety of functionality into boronate derivatives.
The availability of functionalized boronic acid starting materials
and the non-toxic nature of boron served to make boron chemistry
attractive to the radiolabeling community. The reactions proceed
readily at the no-carrier-added level and tolerate a variety of func-
tional groups. One can find examples of boron reagents being used
for the incorporation of carbon-11, nitrogen-13, oxygen-15 [10,11].
Early in 1981, we developed boron-halogen exchange reactions
and found them to be ideal precursors (Scheme 3) [12,13]. Radio-
halogenations of organoboron compounds also have found wide
application in nuclear medicine and biology [4,5,14] due to their
ready availability and lack of toxicity. In addition, halogenation
of organoboranes has played an important role in organic
(Scheme 2) [4,5].
We had established by 1980 that organoboranes could be uti-
lized to incorporate isotopes, but the reactions were not frequently
employed. The reason for the apparent lack of interest was that, in
general, researchers found the preparation of the prerequisite
organoborane reagents to be rather restrictive. Trialkylboranes
were accessible via the hydroboration reaction only if the appro-
*
Corresponding author. Tel.: +1 865 9742997.
E-mail address: kabalka@utk.edu (G.W. Kabalka).
0
022-328X/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2008.11.040

G.W. Kabalka, M.-L. Yao / Journal of Organometallic Chemistry 694 (2009) 1638–1641
1639
"
X"
compound found in the spice, Turmeric, may be responsible for the
low, age-adjusted prevalence of Alzheimer’s disease in India (4.4-
fold less than that found in the USA) [33]. Several studies reveal
that curcumin’s anti-fibrillogenic activity involves fibril-binding
as well as destabilization and inhibition of fibril growth. In addi-
tion, favorable brain permeability and satisfactory Ab plaque bind-
ing properties have been predicted from the fluorescence staining
of Ab plaques in brain sections from APPsw transgenic mice admin-
istered curcumin by injection or via their diet [34]. Currently, cur-
cumin is undergoing a Phase II clinical trial in patients with mild to
moderate Alzheimer’s disease [35]. Because of this, we have syn-
thesized iodine-123 labeled curcumin using our recently devel-
oped radiohalogenation technique (Scheme 5) and carried out
preliminary binding studies using amyloid fibrils associated with
non-Alzheimer’s disorders, such as primary (AL) and systemic AA
amyloidosis.
R
B
R X
where X = OH, NH2, CH2OH, halogen, etc.
and R could contain
CO2H,
C
N,
SH, NH2 halogen, etc.
Scheme 1.
R15OH
15O2
R13NH2
R76Br
125I
11CO
R125
I
R11CH2OH
B
R
[
O]
H
2
. Results and discussion
O
R11CR
R123
I
11CN
The syntheses of trifluoroborate precursor (4) and the stable
iodinated curcumin (2) are shown in Scheme 6. Reported proce-
dures [36] were utilized to prepare compound 2. The Aldol conden-
sation of vanillin and an acetylacetone–boron complex gave the
keto-enol intermediate 1 in 66% yield after column chromatography
and recrystallization. In the presence of piperidine, compound 1
coupled readily with 5-iodovanillin to afford the iodocurcumin 2.
Consistent with reported NMR spectra for curcumin and its ana-
O
R11CR
Scheme 2.
oxidant
logues [37,38], compound 2 gives typical enol resonances at
R
B
+
Na*X
R
*X
1
1
6.35 ppm (s) and 6.05 ppm (s) in the H NMR spectrum. This indi-
cates that the enol form is strongly favored by intramolecular H-
bonding in the equilibrium between the diketo and keto-enol forms.
Boron ester 3 was prepared by the reaction of compound 2 with
Scheme 3.
syntheses. For example, it provides a convenient route to substi-
tuted haloarene intermediates of medicinal importance that other-
wise are not accessible [15–17].
bis(pinocolato)diboron in the presence of PdCl
2
(dppf) and KOAc.
Treatment of crude 3 with 10 equiv. of KHF
precursor 4 as a yellow-brown solid.
2
gives trifluoroborate
Radioiodination of trifluoroborate precursor 4 using Na[123I] in
the presence of chloramine-T was carried out at room temperature.
Radiochemically pure iodine-123 labeled curcumin was isolated in
a 15% yield in 40 min. SPECT imaging studies of iodine-123 labeled
curcumin in a cohort of 5H-2/huIL-6 transgenic mice with systemic
AA amyloidosis are currently underway.
In conclusion, a potential amyloid localizing reagent was suc-
cessfully prepared using a stable trifluoroborate precursor. The
methodology reported is readily amenable to kit applications for
the preparation of a wide variety of no-carrier-added radioiodin-
ated amyloid imaging agents.
In 1995, Vedejs et al. reported the first preparation of trifluorob-
orates from boronic acids [18]. The trifluoroborates are remarkably
stable when compared to the corresponding boronic acids, exhibit-
ing shelf lives on the order of years under atmospheric conditions.
And recent studies involving the trifluoroborate derivatives have
demonstrated how the boron reagents themselves tolerate a wide
variety of chemical transformations [19]; these include nucleo-
philic substitution reactions [20], epoxidations [21], Wittig reac-
tions [22], and Click chemistry [23]. The importance of these
reports is that they validate the fact that boronated intermediates
can ‘‘carry” a plethora of pharmaceutically important functional
groups late into reaction sequences.
In a continuation of our studies focused on the radiohalogen-
ation of organoboron compounds, we reported that organotrifluo-
roborates are suitable radiohalogenation precursors (Scheme 4)
3
. Experimental
All glassware was dried in an oven at 120 °C and flushed with
[
24–28]. We have applied the new chemistry to a number of useful
dry argon. All reactions were carried out under an argon atmo-
sphere. DMSO was distilled over CaH . Other reagents were pur-
chased from commercial sources and used as received. Products
were purified by flash chromatography using silica gel (60Å,
agents including our recent synthesis of an iodine-123 labeled
refecoxib agent [29] and iodostyrylbenzoxazole [30].
In addition, the facile interconversion [18,31,32] between boro-
nic acids, boronic esters and trifluoroborates is extremely attrac-
tive since one can utilize whichever precursor is most effective
when considering radiopharmaceutical preparations.
2
1
13
2
30–400 mesh). H NMR and C NMR were obtained utilizing a
Bruker 250 MHZ (proton) multinuclear analytical NMR.
Recent studies suggested that the anti-fibrillogenic and anti-
oxidant effects of curcumin, a non-steroidal and anti-inflammatory
3.1. Synthesis of 1
2
,4-Pentanedione (6.0 g, 60 mmol) and B O (1.39 g, 20 mmol)
2 3
were dissolved in ethyl acetate (40 mL) and the solution stirred
at 80 °C for 30 min. To this mixture was added vanillin (3.0 g,
Na76Br
Na123
Chloramine-T
I
76Br
123I
R
RBF3K
R
Chloramine-T
2
(
0 mmol, dissolved in 40 mL of ethyl acetate) and (n-BuO)
4.6 g, 20 mmol). After stirring for 30 min at 80 °C, n-butylamine
(1.46 g, 20 mmol) was added dropwise to the mixture which was
3
B
R: Aryl, Alkenyl, alkynyl
Scheme 4.

1
640
G.W. Kabalka, M.-L. Yao / Journal of Organometallic Chemistry 694 (2009) 1638–1641
1
23
3
1
23
Scheme 5.
O
OH
MeO
HO
CHO
O
O
MeO
HO
1
O
MeO
HO
H
O
OH
Pd(dppf)Cl2
MeO
HO
OMe
OH
I
(
-
bispinacolato)
diboron
2
I
O
OH
O
OH
MeO
HO
OMe
OH
MeO
HO
OMe
OH
KHF2
3
4
B
BF3K
O
O
Scheme 6.
allowed to stir at 100 °C for 1 h. The mixture was then treated with
N aqueous HCl (10 mL) at 50 °C and stirred at that temperature
for 30 min. The mixture was extracted with ethyl acetate, washed
with water, and then dried over anhydrous Na SO . Flash column
colato)diboron (145 mg, 0.57 mmol). The flask was flushed with ar-
gon and then charged with dry DMSO (5 mL). After stirring for
15 min, compound 2 (256 mg, 0.52 mmol, dissolved in 5 mL
DMSO) was added to the reaction mixture. The mixture was heated
at 80 °C for 20 h and then cooled to room temperature. After re-
moval of the solvent under vacuum, followed by washing sequen-
tially with water and ethyl acetate, crude 3 was obtained. Due to
its very poor solubility, the NMR of compound 3 was not obtained.
1
2
4
chromatography (3:1 hexanes–ethyl acetate), followed by recrys-
tallization from ethanol and water, gave 1 (3.1 g, 66%) as a yellow
1
solid. H NMR (CDCl
3
): 15.5 (s, 1H), 7.53 (d, J = 15.6 Hz, 1H), 7.11–
6
.91 (m, 3H), 6.33 (d, J = 15.6 Hz, 1H), 5.89 (s, 1H), 5.63 (s, 1H), 3.94
(
s, 3H), 2.16 (s, 3H).
3.4. Synthesis of compound 4
3.2. Synthesis of 2
Crude 3 (obtained as described above), DMF (10 mL), and meth-
5
-Iodovanillin (1.7 g, 6.0 mmol) and B
2
O
3
(690 mg, 10 mmol)
anol (10 mL) were added to a round-bottomed flask and cooled to
0 °C. To this mixture, a KHF (0.40 g, 5.2 mmol) solution in water
were dissolved in ethyl acetate (10 mL) at 80 °C, and to this mix-
ture was added an ethyl acetate solution (10 mL) of 1 (1.17 g,
.0 mmol) and (n-BuO) B (2.3 mL, 10 mmol). After stirring for
3
0 min, the mixture was treated with piperidine (170 mg,
.0 mmol) at 80 °C for 30 min and then with 0.4 N aqueous HCl
7 mL) at 50 °C for 30 min. The reaction mixture was extracted
with ethyl acetate. Removal of the solvent gave a dark brown solid.
After washing with hot water (200 mL) and then hot methanol
2
(8 mL) was added dropwise. The mixture was stirred at room tem-
perature for 12 h. Removal of the solvents under vacuum, followed
by washing sequentially with water (10 mL) and methanol (3 mL),
yielded crude 4 as a yellow-brown solid. Due to its very poor sol-
ubility, the NMR of compound 4 was not obtained and it was used
directly in the next step.
5
3
2
(
(
50 mL), an orange solid (1.8 g, 73%) was obtained. (Note: The
3.5. Preparation of the Iodine-123 labeled 2
NMR spectrum of compound 2 is different from the reported one
À3
given in Ref. [36]).
A solution of 4 (100
l
L of 5.2 Â 10 M solution in 50% aqueous
1
H NMR (DMSO-d
6
): 16.35 (s, br, 1H), 10.11 (s, 1H), 9.66 (s, 1H),
THF) was placed in a 2 mL Wheaton vial containing no-carrier-
added Na I (37 M Bq in 0.1% aqueous NaOH). Chloramine-T
(1.0 mg) was added to the reaction vial which was sealed and cov-
ered with aluminum foil. The reaction mixture was stirred for
15 min at room temperature and then aqueous sodium thiosulfite
13
123
7
(
.65–6.71 (m, 9H), 6.05 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H). C NMR
DMSO-d ): 183.8, 182.4, 149.4, 148.5, 148.0, 147.2, 141.2, 138.9,
6
1
5
31.4, 128.3, 126.3, 123.0, 122.3, 120.9, 115.7, 111.5, 100.9, 84.7,
6.3, 55.7.
À4
(
100
l
L of a 1.0 Â 10 M solution) was added to destroy residual
3.3. Synthesis of 3
molecular iodine. The crude radiolabeled product was isolated by
passing it through a silica gel cartridge using ethyl acetate as elu-
ant. The total synthesis time was about 40 min. The radiochemical
yield was 15%.
2
Into a 50 mL dried round-bottomed flask was added PdCl (dppf)
(
11.5 mg, 0.016 mmol), KOAc (154 mg, 1.57 mmol), and (bispina-

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Acknowledgement is made to the US Department of Energy, the
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