Study on the compounds containing 19F and 10B atoms in a single molecule for the application to MRI and BNCT

Article abstract of DOI:10.1016/j.bmc.2005.10.062

Magnetic resonance imaging (MRI) and boron-neutron capture therapy (BNCT) are quite attractive techniques for diagnosis and treatment of cancer, respectively. In order to progress the study on both MRI and BNCT, the novel compounds containing ¹⁹

Full text of DOI:10.1016/j.bmc.2005.10.062

Bioorganic & Medicinal Chemistry 14 (2006) 3258–3262
19
10
Study on the compounds containing F and B atoms
in a single molecule for the application to MRI and BNCT
Yoshihide Hattori,a Tomoyuki Asano,b Yoko Niki,c Hirofumi Kondoh,c
Mitsunori Kirihata,b Yoshihiro Yamaguchia and Tateaki Wakamiyaa,*
aFaculty of Science and Technology, Kinki University, Higashi-osaka, Osaka 577-8502, Japan
bGraduate School of Life and Environmental Sciences, University of Osaka Prefecture, Sakai, Osaka 599-8231, Japan
cBio-Research, Inc., Kobe, Hyogo 650-0047, Japan
Received 31 August 2005; revised 11 October 2005; accepted 11 October 2005
Available online 3 February 2006
Abstract—Magnetic resonance imaging (MRI) and boron-neutron capture therapy (BNCT) are quite attractive techniques for diag-
nosis and treatment of cancer, respectively. In order to progress the study on both MRI and BNCT, the novel compounds contain-
ing 19F and 10B atoms in a single molecule were designed and synthesized. In the present paper, the syntheses and the internalization
rates into tumor cells of these compounds are elucidated.
ꢀ 2006 Published by Elsevier Ltd.
H2N
F
CO2H
1. Introduction
H2N
CO2H
F
F
Magnetic resonance imaging (MRI) is commonly used
as a technique for diagnosis of cancer. Recently, MRI
based on the measurement of 19F atom attracts the
attention to the field of diagnostics.1 According to our
preliminary elucidation, dipeptides containing 3-(4-flu-
orophenyl)alanine [Phe(F)] (1) seem to be transferred
into some kinds of tumor cells through the oligopeptide
transporter. Furthermore, dipeptide containing 3-(pen-
tafluorophenyl)alanine [Phe(F5)] (2) was certified to be
detectable by 19F NMR up to lM order concentration.2
These facts suggest that MRI based on 19F NMR mea-
surement of the Phe(F5)-containing peptides internal-
ized into the tumor cells may be accessible as a
promising means for diagnosis of cancer.
F
F
F
Phe(F) (1)
Phe(F5) (2)
H2N
R
H2N
F
R
HO
HO
10B
OH
10Bpa (3) (R=CO2H)
10Bpa-ol (4) (R=CH2OH)
10B
OH
F
10Bpa(2,6F2) (5) (R=CO2H)
10Bpa(2,6F2)-ol (6) (R=CH2OH)
Figure 1. Amino acids and their related compounds containing
fluorine and/or boron-10.
From the standpoint of the treatment of brain cancer or
melanoma, the boron-neutron capture therapy (BNCT)
based on the interaction of 10B isotope and neutron has
been highly noted in recent years.3 At present b-[4-
(10B)boronophenyl]alanine (10Bpa)4 (3) and b-[4-
(10B)boronophenyl]alaninol (10Bpa-ol)5 (4) seem to be
good candidates as the 10B carrier for BNCT.
In order to create novel materials to use practically for
diagnosis and treatment of cancer by means of MRI
and BNCT, respectively, we designed and synthesized
the compounds containing both fluorine and boron-10
atoms in a single molecule such as b-[4-(10B)borono-2,6-
difluorophenyl]alanine [10Bpa(2,6F2)] (5) or b-[4-(10B)
borono-2,6-difluoropheny 1]alaninol [10Bpa(2,6F2)-ol]
(6) (Fig. 1). In the present paper, we elucidated the synthe-
ses and internalization rates into tumor cells of these
compounds.
Keywords: Magnetic resonance imaging; Boron-neutron capture
therapy; b-[4-(10B)Borono-2,6-difluorophenyl]-alanine; b-[4-(10B)Bor-
ono-2,6-difluorophenyl]alaninol.
*
Corresponding author. e-mail: wakamiya@chem.kindai.ac.jp
0968-0896/$ - see front matter ꢀ 2006 Published by Elsevier Ltd.
doi:10.1016/j.bmc.2005.10.062

Y. Hattori et al. / Bioorg. Med. Chem. 14 (2006) 3258–3262
3259
F
F
F
F
F
CO2H
F
c
a
b
d
e
OTBDMS
OH
OTBDMS
ClMg
F
Br
F
Br
Br
F
Br
F
11
7
8
9
10
CO2Et
F
F
AcHN
F
H2N
F
CO2H
CO2Et
f
OTBDMS
Br
g
h
HO
HO
10B
OH
F
10B
F
HO
HO
10B
OH
F
10B
OH
F
OH
12
13
14
5
Scheme 1. Reagents and conditions: (a) 1—LDA, THF, ꢀ78 ꢁC, 2 h; (2)—CO2, ꢀ78 ꢁC, 30 min, 86.8%. (b) 1— ClCO2CH(CH3)2, Et3N, THF, 1.5 h,
ꢀ10 ꢁC; (2)— NaBH4, H2O, 0 ꢁC, 4 h, 94.8%. (c) TBDMS-Cl, H-imidazole, DMF, rt, 6 h, 90.4%. (d) iPrMgCl, THF, 0 ꢁC, 1 h. (e) 10B(OMe)3, rt,
24 h, 93.7%. (f) 1—66% AcOH aq, rt, 8 h; 2—PBr3, Et2O, 0 ꢁC, 4 h, 94.2%. (g) Diethyl acetamidomalonate, 60% NaH, THF, 0 ꢁC then reflux, 3 h,
92.7%. (h)1—3 M HCl, 80 ꢁC, 27 h; (2)—propylene oxide, iPrOH, rt, 6 h, 73.7%.
2. Chemistry
acetamidomalonate proceeded appreciably using 60%
NaH, instead of NaOEt, as base. Acid hydrolysis of
the reaction product 14 gave 10Bpa(2,6F2) (5).
The synthesis of 5 was first carried out by the conven-
tional method based on the reaction of alkyl halide with
diethyl acetamidomalonate as shown in Scheme 1.
The amino acid 5 was then converted into the alcohol
derivative 17 as shown in Scheme 2. The a-amino group
of 5 was protected with the Boc group, and the carboxyl
group was reduced to the alcohol derivative 17 through
the mixed acid anhydride (16).9 The Boc group was
cleaved by 4 M HCl/AcOEt to give 10Bpa(2,6F2)-ol
(18) as HCl salt.
1-Bromo-3,5-difluorobenzene (7) was reacted with lithi-
um diisopropyl amide (LDA) and then CO2 to give 4-
bromo-2,6-difluorobenzoic acid (8).6 The benzoic acid
derivative 8 was converted into the benzylalcohol deriv-
ative 9, and then the alcohol group was protected with
the TBDMS group to give the silyl ether derivative 10.
In the next step, the preparation of phenylboric acid
derivative 12 was first carried out by lithiation of 10 with
nBuLi and TMEDA, followed by addition of
10B(OMe)3. Although this reaction gave mainly m-boro-
nated and m,m0-diboronated compounds rather than
p-boronated one, the halogen-metal exchange reaction7
between 10 and isopropyl-magnesium chloride produced
12 in excellent yield.
3. Results and discussion
Incorporation amount and cyctotoxicity of 10Bpa(2,6F2)
and 10Bpa(2,6F2)-ol were examined using three kinds of
cancer cells, C6 (rat glioma), HeLa (human epithelio-
ma), and KB (human squamous cell carcinoma).
Boron concentration incorporated into three cancer cells
was shown in Figure 2. In C6 cell, the amount of both
Treatment of 12 with 66% aqueous AcOH cleaved the
TBDMS group, and the alcohol derivative thus ob-
tained was brominated8 with PBr3 to give the benzyl-
bromide derivative 13. The coupling of 13 with diethyl
10Bpa
10Bpa(2,6F2)
10Bpa(2,6F2)-ol
C6
O
O
BocHN
F
CO2H
BocHN
F
O
OEt
a
b
5
HO
HO
10B
OH
F
10B
OH
F
KB
15
16
BocHN
F
CH2OH
. H2N
F
CH2OH
HCl
HeLa
c
d
HO
HO
10B
OH
F
10B
OH
F
17
18
0
0.2
0.4
0.6
0.8
Boron concentration ( g B / 107 cells)
Scheme 2. Reagents and conditions: (a) (Boc)2O, Na2CO3, acetone,
H2O, rt, 7 h, 97.3%. (b) ClCO2Et, NMM, THF, ꢀ10 ꢁC, 10 min. (c)
NaBH4, MeOH, 0 ꢁC, 1 h, 80.1%. (d) 4 M HCl/AcOEt, rt, 30 min,
92.6%.
μ
Figure 2. Boron concentration in tumor cells which internalized Bpa,
10Bpa(2,6F2), and 10Bpa(F2)-ol.

3260
Y. Hattori et al. / Bioorg. Med. Chem. 14 (2006) 3258–3262
10Bpa(2,6F2) and 10Bpa(2,6F2)-ol was half of that of
10Bpa. In KB and HeLa, however, the accumulation
amount of these compounds was almost the same as that
of 10Bpa, respectively.
fied with citric acid and diluted with H2O (50 mL) to dis-
solve precipitated inorganic materials. After evaporation
of THF, the aqueous solution was extracted with AcOEt
(40 mL · 3). The combined extracts were washed with sat.
NaHCO3 aq (30 mL · 3) and brine (30 mL · 3), and dried
over anhydrous MgSO4. The solution was concentrated
in vacuo, and the residue was purified by silica-gel column
chromatography (silica gel: 60 g, hexane/AcOEt = 9:1) to
give 9 as a colorless crystals (1.79 g, 94.8%): mp 38–40 ꢁC.
1H NMR (CDCl3) d 1.95 (t, 1H, J = 6.0 Hz), 4.73 (d, 2H,
J = 6.0 Hz), 7.11 (d, 2H, J = 15.9 Hz); Anal. Calcd for
C7H5BrF2O: C, 37.70; H, 2.26. Found: C, 37.40; H, 2.34.
Cytotoxicity of these compounds toward C6 cell was not
observed in the range of 1–20 mM concentration (data
not shown). These results suggest that the cytotoxicity
of these compounds might almost be equal to that of
10Bpa and also useful for a 10B carrier of BNCT.
4. Experimental
4.1. General
4.2.3. 4-Bromo-2,6-difluorobenzyl alcohol t-butyldi-meth-
ylsilyl ether (10). To a solution of 9 (1.14 g, 7.89 mmol)
in DMF (10 mL) were added 1H-imidazole (644 mg,
9.47 mmol) and TBDMS-Cl (1.31 g, 8.68 mmol), and
the reaction mixture was stirred for 1 h. After evaporation
of the solvent, the residue was dissolved in Et2O (50 mL).
The solution was washedwithH2O (20 mL · 3), and brine
(20 mL · 3), and dried over anhydrous MgSO4. The solu-
tion was concentrated in vacuo, and the residue was puri-
fied by silica-gel column chromatography (silica gel: 40 g,
Silica-gel column chromatography was carried out with
silica gel PSQ100B (Fuji Silysia, Aichi, Japan). 1H NMR
and 19F NMR spectra were measured on a Varian Mer-
cury 300 [300 MHz (1H) and 282 MHz (19F), Varian
Co., Ltd., USA] spectrometer. The chemical shifts in
1H NMR are given in d values from TMS and those
in 19F NMR from TFA used as the internal standard,
respectively. Matrix-assisted laser desorption ionization
time-of-flight mass spectra (MALDI-TOF MS) were ob-
tained on a KRATOS KOMPACT MALDI IV mass
spectrometer (Shimadzu Co. Ltd., Kyoto, Japan). Mea-
surement of high resolution mass was carried out by
fast-atom bombardment mass spectrometry (FAB-MS)
using a JEOL JMS-700 TKM mass spectrometer (JEOL
Co. Ltd., Tokyo, Japan). 10B(OMe)3 was given by Stella
Chemifa Corporation (Osaka, Japan).
1
hexane) to give 10 as colorless oil (1.89 g, 92.6%): H
NMR (CDCl3) d 0.10 (s, 6H), 0.88 (s, 9H), 4.77 (s, 2H),
7.11 (d, 2H, J = 15.9 Hz).
4.2.4. 4-(10B)Borono-2,6-difluorobenzyl alcohol t-butyl-
dimethylsilyl ether (12). To a solution of 10 (6.87 g,
20.4 mmol) in anhydrous THF (40 mL) was added a
solution of 2.00 M iPrMgCl in THF (10.2 mL,
20.4 mmol) at 0 ꢁC under Ar atmosphere. After stirring
for 1 h at 0 ꢁC, to the reaction mixture was added
10B(OMe)3 (1.62 g , 15.7 mmol), and the solution was
stirred for 24 h. The reaction mixture was acidified with
10% aqueous citric acid, and THF was removed by
evaporation in vacuo. The aqueous solution was extract-
ed with Et2O (60 mL · 3), and the extract was dried over
anhydrous MgSO4. The solution was concentrated in
vacuo, and the residue was purified by silica-gel column
chromatography (silica gel: 180 g, hexane/AcOEt = 1:1)
to give 12 as colorless oil (5.77 g, 93.7%): 1H NMR
(CD3COCD3) d 0.10 (s, 6H), 0.88 (s, 9H), 4.77 (s, 2H),
6.95 (d, 2H, J = 15.9 Hz), 7.62 (s, 2H).
4.2. Synthesis
4.2.1. 4-Bromo-2,6-difluorobenzoic acid (8). To a solution
of diisopropylamine (4.82 g, 25.0 mmol) in anhydrous
THF (35 mL) was consecutively added a solution of
1.60 M nBuLi in hexane (15.6 mL, 25.0 mmol) and 7
(2.53 g, 25.0 mmol) under Ar atmosphere at ꢀ78 ꢁC.
After stirring for 2 h at ꢀ78 ꢁC, CO2 gas (0.02 MPa)
was bubbled into the reaction mixture for 30 min under
cooling at ꢀ78 ꢁC. After evaporation of the solvent, the
residue was dissolved in water (50 mL), and the solution
was washed with Et2O (20 mL · 3). The aqueous layer
was acidified with concd HCl to pH 1 and extracted with
CH2Cl2 (20 mL · 3). The combined extracts were dried
over anhydrous MgSO4 and concentrated in vacuo.
The crystalline residue was recrystallized from benzene
and hexane to give 8 as yellow crystals (5.15 g, 86.8%):
mp 195–197 ꢁC. 1H NMR (CDCl3) d 7.28–7.42 (m,
2H); Anal. Calcd for C7H3BrF2O2: C, 35.47; H, 1.28.
Found: C, 35.49; H, 1.50.
4.2.5. 4-(10B)Borono-2,6-difluorobenzyl bromide (13). A
solution of 12 (1.59 g, 5.26 mmol) in 66% AcOH
(100 mL) was stirred for 8 h. The reaction mixture was
concentrated in vacuo, and the residue was dissolved
in Et2O (100 mL). To the solution was added PBr3
(1 mL) slowly at 0 ꢁC, and the mixture was stirred for
4 h at 0 ꢁC. To the reaction mixture was added ice-
cooled water (50 mL), and the solution was extracted
with Et2O (40 mL · 3). The combined extracts were
washed with water (50 mL · 3) and brine (50 mL · 3),
and dried over anhydrous MgSO4. The solution was
concentrated in vacuo, and the residue was purified by
silica-gel column chromatography (silica gel: 50 g,
CHCl3/Me0H = 9:1) to give 13 as colorless crystals
4.2.2. 4-Bromo-2,6-difluorobenzyl alcohol (9). To a solu-
tion of 8 (2.00 g, 12.7 mmol) and Et3N (1.93 g,
19.1 mmol) in anhydrous THF (100 mL) was added
ClCO2CH(CH3)2 (2.34 g, 19.1 mmol) dropwise for
10 min at ꢀ20 ꢁC. After stirring for 1.5 h at ꢀ10 ꢁC, to
the reaction mixture was added water (50 mL) at
ꢀ10 ꢁC, and then to the solution was added slowly
NaBH4 (1.83 g, 50.8 mmol) at 0 ꢁC. After stirring for
4 h at room temperature, the reaction mixture was acidi-
1
(1.24 g, 94.2%): mp 60–65 ꢁC. H NMR (CD3COCD3)
d 4.64 (s, 2H), 7.43 (d, 2H, J = 8.4 Hz); Anal. Calcd
for C7H6 10BBrF2O2: C, 33.63; H, 2.42. Found: C,
33.97; H, 2.77.

Y. Hattori et al. / Bioorg. Med. Chem. 14 (2006) 3258–3262
3261
4.2.6. 2-Acetylamino-2-[4-(10B)borono-2,6-difluoro)]-phen-
ylmethylmalonic acid diethyl ester (14). To a suspension of
60% NaH (122 mg, 3.65 mmol) in anhydrous THF (5 mL)
was added a solution of diethyl acetamido-malonate
(693 mg, 3.19 mmol) in anhydrousTHF (5 mL) at0 ꢁC un-
der Ar atmosphere. After stirring for 1 h, to the reaction
mixture was added 13 (762 mg, 3.04 mmol) at 0 ꢁC, and
the suspension was refluxed for 3 h. The reaction mixture
was acidified with 1 M HCl and THF was removed by
evaporation in vacuo. The residual aqueous solution was
extracted with AcOEt (30 mL · 3), and the combined ex-
tracts were washed with 10% aqueous citric acid
(20 mL · 3), saturated NaHCO3 (20 mL · 3) and brine
(20 mL · 3). The organic layer was dried over anhydrous
MgSO4, and the solution was concentrated in vacuo. The
residue was purified by silica-gel column chromatography
(silica gel: 50 g, benzene/acetone = 3:1) to give 13 as color-
N-methylmorpholine (511 mg, 5.45 mmol) and ClCO2Et
(591 mg, 5.45 mmol) at ꢀ10 ꢁC. After stirring for
10 min at ꢀ10 ꢁC, to the reaction mixture were added
NaBH4 (412 mg, 10.9 mmol) and MeOH (5 mL) at
ꢀ10 ꢁC, and the mixture was stirred for 1 h at room tem-
perature. After evaporation of organic solvents in vacuo,
the residual aqueous solution was extracted with AcOEt
(40 mL · 3). The combined extracts were washed with
10% aqueous citric acid (15 mL · 3) and brine
(15 mL · 3), and dried over anhydrous MgSO4. The solu-
tion was concentrated in vacuo, and the residue was puri-
fied by silica-gel column chromatography (silica gel; 70 g,
CHCl3:MeOH = 9:1) to give 17 as a colorless amorphous
solid (961 mg, 80.1%): 1H NMR (CD3COCD3) d 1.27 (s,
9H), 2.85–3.07 (m, 2H), 3.49–3.75 (m, 2H), 3.91–4.09 (m,
1H), 7.41 (d,2H,J = 9.0 Hz).
1
less crystals (1.09 g, 92.7%): mp 131–134 ꢁC. H NMR
4.2.10. b-[4-(10B)Borono-2,6-difluorophenyl]alaninol hydro-
chloride (18). The compound 17 (900 mg, 2.72 mmol) was
dissolved in 4 M HCl/AcOEt (10 mL) and the reaction
mixture was stirred for 10 min. The solution was concen-
trated in vacuo, and the residue was dissolved in H2O
(20 mL). The aqueous solution was washed with Et2O
(10 mL · 3) and concentrated in vacuo. The crystalline
residue was recrystallized from MeOH to give 17 as col-
orless crystals (671 mg, 92.6%): mp 225–243 ꢁC (dec). 1H
NMR (D2O) d 2.83–2.97 (m, 2H), 3.52–3.49 (m, 2H),
3.62–3.70 (m, 1H), 7.13 (dd, 2H, J = 7.5 Hz, 5.1 Hz; 19F
NMR (D2O) d-119; MALDI-TOF MS: found m/z
231.7 [M+H]+ (calcd for C9H12 10BF2NO3+H: 232.1);
Anal. Calcd for C9H13 10BClF2NO3: C, 40.54; H, 4.91;
N, 5.25. Found: C, 40.42; H, 5.00; N 5.40.
(CD3COCD3) d 1.23 (t, 6H, J = 6.9 Hz), 1.94 (s, 3H),
3.67 (s, 2H), 3.73–4.27 (m, 4H), 7.32 (d, 2H, J = 8.4 Hz),
7.50 (br, 2H); Anal. Calcd for C9H10 10BF2NO4: C,
38.58; H, 5.04; N, 5.00. Found: C, 38.27; H, 4.96; N 4.87.
4.2.7. b-[4-(10B)Borono-2,6-difluorophenyl]alanine (5). A
solution of 14 (3.00 g, 7.77 mmol) in 3 M HCl (2 L) was
stirred for 27 h at 100 ꢁC. The reaction mixture was con-
centrated in vacuo, and the residual solid was dissolved in
3 M HCl (500 mL). The solution was washed with Et2O
(100 mL · 3) and concentrated in vacuo. The residual sol-
id was dissolved in iPrOH and to the solution was added
propylene oxide (900 mg, 15.5 mmol). After stirring for
6 h, the reaction mixture was concentrated in vacuo.
The crystalline residue was recrystallized from water to
give 5 as colorless crystals (1.40 g, 73.7%): mp 292–
4.3. Cells and cell culture
1
297 ꢁC (dec). H NMR (D2O) d 3.09–3.27 (m, 2H), 4.12
(t, 1H, J = 6.9 Hz), 7.12 (dd, 2H, J = 6.6 Hz, 4.8 Hz);
19F NMR (D2O) d-119; MALDI-TOF MS: found m/z
246.5 [M+H]+ (calcd for C9H10 10BF2NO4+H: 246.1);
Anal. Calcd for C9H10 10BF2NO4 Æ 2H2O: C, 38.58; H,
5.04; N, 5.00. Found: C, 38.27; H, 4.96; N 4.87.
HeLa (human adenocarcinoma) cell, KB (human epi-
dermal carcinoma) cell, and C6 (rat glioma) cell lines
were used in the boron incorporation study. Cells were
cultured in Dulbeccoꢀs minimum essential medium
(DMEM) supplemented with 10% fetal bovine serum,
2 mM glutamine, and 24 mM sodium bicarbonate at
37.C in a 5% CO2 atmosphere.
4.2.8. Na-t-Butoxycarbonyl-b-[4-(10B)borono-2,6-di-fluor-
ophenyl]alanine (15). To a solution of 5 (1.00 g, 4.10 mmol)
in water (50 mL) and acetone (50 mL) were added Na2CO3
(478 mg, 4.51 mmol) and Boc2O (984 mg, 4.51 mmol), and
the reaction mixture was stirred for 8 h. The reaction mix-
ture was acidified with 10% aqueous citric acid, and ace-
tone was removed by evaporation in vacuo. The aqueous
solution was extracted with AcOEt (40 mL · 3), and the
combined extracts were washed with 10% aqueous citric
acid (30 mL · 3) and brine (30 mL · 3). The organic layer
was dried over anhydrous MgSO4, and the solution was
concentrated in vacuo. The crystalline residue was recrys-
tallizedfromAcOEtandhexanetogive15ascolorlesscrys-
tals (1.37 g, 97.2%): mp 280–296 ꢁC (dec). 1H NMR
(CD3COCD3) d 1.29 (s, 9H), 3.06–3.30 (m, 2H), 4.24–
4.33 (m, 1H), 7.42 (d, 2H, J = 9.3 Hz); Anal. Calcd for
C14H18 10BF2NO6: C, 48.84; H, 5.27; N, 4.07. Found: C,
48.08; H, 5.39; N 3.91.
Cells in monolayer were harvested with 0.25% trypsin/
0.02% EDTA in Ca2+-free phosphate-buffered saline
(PBS).
4.4. In vitro boron incorporation into cultured tumor cells
Cultures were inoculated with 5 · 106 cells/dish, and
cells were grown for 24 h in DMEM. The medium was
replaced with each medium containing boron com-
pounds such as 10Bpa(2,6F2), 10Bpa(2,6F2)-ol, and
10Bpa (final concentration was 1.0 mM in each case).
The cells were cultured for 24 h, and the medium was re-
moved by aspiration. Cells were washed three times with
PBS, harvested by trypsinization, and cell number was
counted. Each sample containing 1 · 107 cells was added
to a mixture consisting of HClO4 (60%, 0.3 ml) and
H2O2 (31%, 0.6 ml), and then the mixture was heated
at 75 ꢁC for 1 h. After filtration of the mixture through
membrane filter (Millipore, 0.45 lm), boron concentra-
tion in the filtrate was measured by ICP-AES.
4.2.9. Na-t-Butoxycarbonyl-y3-[4-(10B)borono-2,6-di-fluor-
ophenyl]alaninol (17). To a solution of 15 (1.25 g,
3.63 mmol) in anhydrous THF (50 mL) were added

3262
Y. Hattori et al. / Bioorg. Med. Chem. 14 (2006) 3258–3262
1998, 98, 1515; (b) Barth, R. F.; Yang, W.; Adams, D. M.;
Acknowledgments
Rotaru, J. H.; Shukla, S.; Sekido, M.; Tjarks, W.; Frest-
ermaker, R. A.; Ciesielski, M.; Nowrocky, M. M.; Coderre,
J. A. Cancer Res. 2002, 62, 3159; (c) Kato, I.; Ono, K.;
Sakurai, Y.; Ohmae, M.; Maruhashi, A.; Imahori, Y.;
Kirihata, M.; Nakazawa, M.; Yura, Y. Appl. Radiat. Isot.
2004, 61, 1083.
This work was supported in part by Grants-in-Aid for
Scientific Research Nos. 11680593 and 11680678 from
the Ministry of Education, Science and Culture.
4. Snyder, H. R.; Reedy, A. J.; Lennarz, W. J. J. Am. Chem.
Soc. 1958, 80, 835.
References and notes
5. Masunaga, S.; Ono, K.; Kirihata, M.; Takagaki, M.;
Sakurai, Y.; Kinashi, Y.; Kobayashi, T.; Nagasawa,
H.; Uto, Y.; Hori, H. Jpn. J. Cancer Res. 2001, 92,
996.
6. Mongin, F.; Schlosser, M. Tetrahedron Lett. 1996, 37, 6551.
7. Matondo, H.; Souirti, S.; Baboulene, M. Synth. Commun.
2003, 33, 795.
8. Naruta, Y.; Uno, H.; Maruyama, K. Tetrahedron Lett.
1981, 22, 5221.
9. Kabalka, W. G. Synthesis 1990, 4, 299.
1. (a) Sassa, T.; Suhara, T.; Ikehira, H.; Obata, T.; Griard, F.;
Tanada, S.; Okubo, Y. Psychiatry Clin. Neurosci. 2002, 56,
637; (b) Higuchi, M.; Iwata, N.; Matsuba, Y.; Sato, K.;
Sasamoto, K.; Saido, C. T. Nat. Neurosci. 2005, 8, 527.
2. Hattori, Y.; Yamaguchi, Y.; Yamamoto, H.; Asano, T.;
Kirihata, M.; Takagaki, M.; Wakamiya, T. Peptide Sci.
2004 2005, 411.
3. (a) Soloway, H. A.; Tjarks, W.; Barnum, A. B.; Rong, F.;
Barth, F. R.; Codogni, M. I.; Wilson, J. G. Chem. Rev.