Development of the first and practical method for enantioselective synthesis of 10B-enriched p-borono-l-phenylalanine

Article abstract of DOI:10.1016/j.tetlet.2008.05.108

At present p-(¹⁰B)borono-l-phenylalanine (l-¹⁰Bpa) is used clinically as an excellent ¹⁰B carrier for BNCT; however, its enantioselective synthesis has not been reported yet. The present Letter describes the first and prac

Full text of DOI:10.1016/j.tetlet.2008.05.108

Tetrahedron Letters 49 (2008) 4977–4980
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Development of the first and practical method for enantioselective
synthesis of 10B-enriched p-borono-L-phenylalanine
Yoshihide Hattori a, Tomoyuki Asano a, Mitsunori Kirihata a, Yoshihiro Yamaguchi b, Tateaki Wakamiya b,
*
a Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka 599-8231, Japan
b Faculty of Science and Technology, Kinki University, Higashi-osaka, Osaka 577-8502, Japan
a r t i c l e i n f o
a b s t r a c t
At present p-(10B)borono-
L-phenylalanine (
L
-
10Bpa) is used clinically as an excellent 10B carrier for BNCT;
Article history:
Received 25 March 2008
Revised 14 May 2008
Accepted 16 May 2008
Available online 28 May 2008
however, its enantioselective synthesis has not been reported yet. The present Letter describes the first
and practical method for enantioselective synthesis of 10B-enriched
synthon in good total yield and high optical purity.
L
-Bpa using Z-L-Ser–OMe as the chiral
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
p-Boronophenylalanine
BNCT
Enantioselective synthesis
1,8-Diaminonaphtalene
1. Introduction
2. Results and discussion
Boron neutron capture therapy (BNCT) based on the selective
accumulation of 10B compounds in tumor cells and the subse-
quent irradiation with thermal neutron is highly noted as one
of useful techniques for treatment of cancer.1–3 So far p-
To date, three synthetic approaches of L-Bpa with naturally
occurring boron atom7 utilizing the enantioselective method have
been known. For example, Kirihata and co-workers reported the
enantioselective synthesis of
of 4-boronobenzylbromide with the chiral derivative prepared
from
-valine.8 However, this method needs further enzymatic res-
olution to obtain optically pure -Bpa, since the enantioselectivity
L-Bpa based on the coupling reaction
(
10B)boronophenylalanine (10Bpa) (1) in which boron atom is en-
riched with 10B isotope had been developed as an excellent 10B
carrier for BNCT (Fig. 1). Since the incorporating amount of
L
L
L
-
10Bpa into cancer cells is higher than that of
D
-
10Bpa or
of the coupling reaction is slightly low. Furthermore, Yamamoto
and co-workers reported the method based on palladium catalyzed
DL- L-
10Bpa,4 10Bpa is now being used clinically for the treatment
of patients with malignant brain tumor and/or melanoma owing
coupling reaction of pinacolborane with 4-iodo-
derivatives.9 This method is also not suitable for the synthesis of
L-
10Bpa, because 10B-enriched pinacolborane is not commercially
L-phenylalanine
to the selective accumulation and low toxicity.5 At present, com-
mercially available
L
-
10Bpa is prepared by the enzymatic resolu-
tion of the racemic precursor.6
available and its synthetic method is not reported as well. In
another case, Malan and Morin reported an interesting method
utilizing the Negishi coupling reaction of iodophenylborate and
L
-iodoalanine derivatives.10 However, this method is also unsuit-
able for the synthesis of L-
10Bpa, because both 10B-enriched BI3
H2N
CO2H
and 1,3-diphenylpropane-1,3-diol used as the protecting group of
boron are not commercially available. Consequently, all these
HO
methods are not applicable to the synthesis of 10B-enriched
L
-Bpa.
Therefore, we examined a development of efficient method for
enantioselective synthesis of
10Bpa utilizing the Negishi reaction
based on the coupling of 4-(10B)borono-iodobenzene derivative
10B
OH
L-10Bpa (1)
L
-
with 3-iodo-L-alanine [L-Ala(3I)] derivative. The most important
Figure 1. The structure of L-
10Bpa (1).
advantage of the present method is that 10B(OMe)3 as 10B source
to prepare 4-(10B)boronoiodobenzene is commercially available.
Further
synthesis of
L
-Ala(3I) can be readily prepared from
L-serine. Thus, the
* Corresponding author. Tel.: +81 6 6721 2332; fax: +81 6 6723 2721.
E-mail address: wakamiya@chem.kindai.ac.jp (T. Wakamiya).
L
-
10Bpa was carried out as shown in Schemes 1 and 2.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.108

4978
Y. Hattori et al. / Tetrahedron Letters 49 (2008) 4977–4980
Table 1
HO
10B
HO
Yields of the Negishi coupling on various reaction conditions
a
b
I
I
I
ZHN
CO Me
2
ZHN
R
6 : R=I
6': R=ZnI
CO Me
2
H
N
2
3
4, Catalyst
DMF
10B
NH
H
N
10B
I
7
N
H
Entry
Catalyst
Conditions
Yield (%)
4
1
2
3
4
5
Pd(PPh3)2Cl2 (0.06 equiv)
Pd(PPh3)2Cl2 (0.06 equiv)
Pd(PPh3)4 (0.06 equiv)
Pd(PPh3)4 (0.06 equiv)
Pd2(dba)3 (0.03 equiv)
P(o-tolyl)3 (0.10 equiv)
Pd2(dba)3 (0.06 equiv)
P(o-tolyl)3 (0.10 equiv)
rt, 24 h
70 °C, 12 h
rt, 24 h
70 °C, 3 h
rt, 12 h
Trace
6.88
Trace
42.7
Scheme 1. Reagents and conditions: (a) (i) n-BuLi (1.00 equiv), THF, ꢁ78 °C, 30
min; (ii) 10B(OMe)3, ꢁ78 °C, 5 h; (b) 1,8-diaminonaphtalene, THF, rt, 12 h, 57.7% (2
steps from 2).
78.4
6
70 °C, 3 h
72.7
First, 1,4-diiodobenzene (2) was allowed to react with
10B(OMe)3 to give 4-(10B)boronoiodobenzene (3). The borono
group of 3 was then protected with 1,8-diaminonaphtalene that
was developed as a masking agent in the Suzuki–Miyaura cross
coupling reaction by Suginome and co-workers11 to give 4-[2,3-
dihydro-1h-naphtho[1,8-de]-1,3-diaza-2-(10B)borinyl]iodobenzene
(4) (Scheme 1).
method are currently being undertaken, and the results will be re-
ported soon elsewhere.
Next, Z-L L-Ser–OMe
-Ala(3I)–OMe (6)12 was prepared from Z-
3. Experimental
3.1. General
(5)13 (Scheme 2), and the compound 6 was coupled with the arylio-
dide 4 via Zn adduct 60 by employing the Negishi coupling reaction
a
to give N -benzyloxycarbonyl-p-[2,3-dihydro-1H-naphtho[1,8-de]-
1,3-diaza-2-(10B)borin-yl]-
L-phenylalanine methyl ester (7). To
All of the melting points are uncorrected and were measured by
Yanaco MP-J3 (Yanaco Co., Ltd, Kyoto, Japan). Silica-gel column
chromatography was carried out with silica gel PSQ100B (Fuji Sily-
sia Chemical Ltd, Aichi, Japan). 1H NMR spectra were measured on
a Varian Mercury 300 (300 MHz, Varian Co., Ltd, USA) spectrome-
ter. The chemical shifts in 1H NMR are given in d values from
TMS used as the internal standard. HPLC analysis was performed
on a LaChrom Elite (Hitachi high-Technologies Corporation, Tokyo,
find the optimal conditions for the Negishi coupling, we exam-
ined the relationship between the yields and the catalysts on var-
ious reaction conditions as shown in Table 1. The reaction scarcely
proceeded in the presence of Pd(PPh3)2Cl2 (entries 1 and 2) as a
catalyst. When the reaction was carried out at 70 °C with Pd(PPh3)4
catalyst, L-
10Bpa derivative 7 was produced in a 42.7% yield (entry
4), although the reaction did not proceed at room temperature (en-
try 3). As a result, the reaction proceeded favorably at rt by the use
of Pd2(dba)3 and P(o-tolyl)3 as catalysts,14 although the yield was
slightly decreased when the reaction was carried out at 70 °C (en-
tries 5 and 6).
Japan) instrument equipped with a CROWNPAK AK CR(+) (5 lm,
0.5 ꢀ 15 cm) (Daicel Chemical Industries, Ltd, Osaka, Japan) with
a flow rate of 0.8 mL/min and detection at 230 nm. Elemental anal-
yses were performed at the Micro Corder JM10 (J-Science Lab. Co.
Ltd, Kyoto, Japan). Optical rotations were measured on a Jasco DIP-
140 polarimeter (JASCO Co., Tokyo, Japan). 10B(OMe)3 was pur-
chased from Stella Chemifa Co. (Osaka, Japan). 1,2-Dibromoethane
and nBuLi were purchased from Nacalai Tesque Inc. (Kyoto, Japan).
1,8-Diaminonaphtalene, TMS-Cl, and propylene oxide were
purchased from Wako Pure Chemical Industries, Ltd (Osaka,
Japan), 1,4-diiodo-benzene, tris(dibenzylideneacetone)dipalladium
[Pd2(dba)3] and tri(o-tolyl)phosphine [P(o-tolyl)3] were purchased
from Sigma–Aldrich Co. (USA).
The diaminonaphthyl group of compound 7 was cleaved with
2 M H2SO4 in advance to give Z-
carbonyl and methyl groups were simultaneously removed by acid
hydrolysis with 3 M HCl to give
10Bpa (1) (Scheme 2). HPLC anal-
ysis of 1 thus obtained with a chiral column revealed the optical
purity to be >99% (Fig. 2).
L-
10Bpa–OMe (8). The benzyloxy-
L-
As mentioned above, we have succeeded to develop the first
method for the enantioselective synthesis of L- L-
10Bpa (1) from Z-
Ser–OMe (5) used as the chiral synthon in 51.0% overall yield. This
method is shorter in the reaction step and higher in the overall
yield compared to the conventional methods for the synthesis of
3.2. 4-[2,3-Dihydro-1H-naphtho[1,8-de]-1,3-diaza-2-(10B)-
borinyl]iodobenzene (4)
L
-Bpa.15
The syntheses of the chiral fluorinated 10Bpa derivatives such as
b-[4-(10B)borono-2-trifluoromethylphenyl]alanine
and b-[4-
10B)borono-2,6-difluorophenyl]alanine16–18 using the present
To a solution of 1,4-diiodo-benzene (2) (10.0 g, 30.3 mmol) in
THF (100 mL) was added n-BuLi (1.6 M solution in hexane,
(
ZHN
CO Me
ZHN
CO Me
2
H N
2
CO H
2
2
ZHN
HO
COOMe
ZHN
CO Me
2
H
N
a
b, c
e
d
HO
HO
10B
NH
10B
OH
10B
OH
I
5
6
8
1
7
Scheme 2. Reagents and conditions: (a) I2, imidazole, PPh3, CH2Cl2, rt, 5 h, 82.7%; (b) activated Zn, DMF, 35 °C, 1.5 h; (c) compound 4, Pd2(dba)3, P(o-tolyl)3, DMF, rt, 12 h,
78.4% (2 steps); (d) 2 M H2SO4, THF, rt, 2 h, 94.6%; (e) (i) 3 M HCl, 80 °C, 17 h; (ii) propylene oxide, iPrOH, rt, 14 h, 83.1%.

Y. Hattori et al. / Tetrahedron Letters 49 (2008) 4977–4980
4979
was filtrated through the Celite, and the filtrate was washed with
H2O (300 mL ꢀ 3) and brine (300 mL ꢀ 3). The organic layer was
dried over anhydrous MgSO4, and concentrated in vacuo. The res-
idue was purified by silica-gel column chromatography (silica
gel: 400 g, hexane and then hexane/AcOEt = 9:1) to give 6 as color-
less amorphous solid (37.2 g, 82.7%): mp 69–71 °C.
A
B
½
a 2D2
ꢂ
ꢁ 6:1ðc1:0; CHCl3Þ. 1H NMR (CD3Cl) d 3.50 (d, J = 3.6 Hz, 2 h),
3.81 (s, 3H), 4.57–4.62 (m, 1H), 5.13 (s, 2H), 5.66 (d, J = 7.5 Hz,
1H), 7.28 (s, 5H). Anal. Calcd for C12H14INO4: C, 39.69; H, 3.89; N,
3.86. Found: C, 39.92; H, 4.20; N, 3.86.
0
5
10
15
20
25
30
Retention Time (min)
a
3.4. N -Benzyloxycarbonyl-p-[2,3-dihydro-1H-naphtho[1,8-de]-
1,3-diaza-2-(10B)borinyl]-
L
-phenylalanine methyl ester (7)
A solution of 1,2-dibromoethane (310 L, 3.60 mmol) in DMF
l
(5 mL) was added to zinc dust (4.71 g, 72.0 mmol) under Ar atmo-
sphere, and the suspension was stirred for 30 min at 90 °C. To the
suspension was added TMS-Cl (129 lL, 3.60 mmol) at room tem-
perature, and the mixture was stirred for 30 min. A solution of 6
(4.38 g, 12.0 mmol) in DMF (10 mL) was added to the reaction
mixture, and the mixture was stirred for 1.5 h at 35 °C. To the
reaction mixture were added 4 (4.01 g, 10.0 mmol), Pd2(dba)3
(274 mg, 0.30 mmol); and P(o-tolyl)3 (304 mg, 1.00 mmol), and
the mixture was stirred for 12 h at room temperature. The reac-
tion mixture was filtered to remove the excess zinc dust, and
the filtrate was diluted with AcOEt (100 mL). The solution was
washed with H2O (40 mL ꢀ 3) and brine (40 mL ꢀ 3), and dried
over MgSO4. The dried extract was concentrated in vacuo, and
the residue was purified by silica-gel column chromatography
(150 g, benzene and then benzene:acetone = 9:1) to give 7 as col-
0
5
10
15
20
25
30
Retention Time (min)
C
orless crystals (4.00 g, 78.4%): mp 115–117 °C.
½
a 2D2
ꢂ
ꢁ0:3
ðc1; MeOHÞ. 1H NMR (300 MHz, CDCl3) d 3.16 (ddd, J = 26.1 Hz,
14.4 Hz, 6.0 Hz, 2H), 3.75 (s, 3H), 4.62 (dd, J = 14.4 Hz, 6.0 Hz,
1H), 5.11 (s, 2H), 5.28 (d, J = 8.1 Hz, 1H), 6.00 (s, 2H), 6.41 (dd,
J = 7.2 Hz, 1.2 Hz, 2H), 7.04–7.17 (m, 6H), 7.32–7.37 (m, 5H),
7.52 (d, J = 7.8 Hz, 2H). Anal. Calcd for C28H2610BN3O4ꢃ0.5CH3-
COCH3: C, 69.81; H, 5.76; N, 8.28. Found: C, 69.54; H, 5.99; N,
8.47.
0
5
10
15
20
25
30
Retention Time (min)
Figure 2. HPLC analysis of 10Bpa with a chiral column; (A) authentic sample of
10Bpa, (B) authentic sample of 10Bpa, (C) synthetic 10Bpa. Analytical
conditions-column: CROWNPAK AK CR(+); eluate: 0.4% aqueous HClO4; flow rate:
0.8 mL/min; detection: UV 230 nm.
DL
-
L-
L-
a
18.9 mL, 30.3 mmol) dropwise under cooling at ꢁ78 °C, and the
solution was stirred for 30 min at ꢁ78 °C. To the reaction mixture
was added 10B(OMe)3 (3.75 g, 36.4 mmol) dropwise under cooling
at ꢁ78 °C, and the solution was stirred for 5 h at ꢁ78 °C. To the
reaction mixture was added saturated aqueous NH4Cl (100 mL),
and the solution was extracted with Et2O (100 mL ꢀ 3). The com-
bined extracts were washed with H2O (100 mL ꢀ 3) and brine
(100 mL ꢀ 3), and dried over anhydrous MgSO4. The dried extract
was concentrated in vacuo, and the residue was dissolved in THF.
To the solution was added 1,8-diaminonaphtalene (4.79 g, 30.3
mmol), and the mixture was stirred for 12 h. The reaction mixture
was concentrated in vacuo, and the residue was purified by silica-
gel column chromatography (silica gel: 200 g, hexane/AcOEt = 9:1)
to give 4 as brown crystals (7.04 g, 57.7%): mp 171–172 °C. 1H NMR
(CDCl3) d 5.98 (s, 2H), 6.41 (dd, J = 7.5 Hz, 1.2 Hz, 2H), 7.05–7.17
(m, 4H), 7.37 (dd, J = 6.6 Hz, 1.8 Hz, 2H), 7.87 (dd, J = 6.6 Hz,
1.8 Hz, 2H). Anal. Calcd for C16H1210BIN2: C, 52.05; H, 3.28; N,
7.59. Found: C, 52.00; H, 3.60; N, 7.46.
3.5. N -Benzyloxycarbonyl-p-(10B)borono-
L
-phenylalanine
methyl ester (8)
To a solution of 7 (3.18 g, 6.23 mmol) in THF (75 mL) was added
2M H2SO4 (75 mL), and stirred for 2 h at room temperature. The
reaction mixture was filtered, and the filtrate was extracted with
AcOEt (50 mL ꢀ 3). The combined extracts were washed with 2M
H2SO4 (50 mL ꢀ 3), saturated aqueous NaHCO3 (50 mL ꢀ 3) and
brine (50 mL ꢀ 3). The organic layer was dried over anhydrous
MgSO4, and concentrated in vacuo. The residue was purified by sil-
ica-gel column chromatography (100 g, CH2Cl2:MeOH = 19:1) to
give 8 as colorless crystals. (2.10 g, 94.6%): mp 190–192 °C.
½
a 2D2
ꢂ
ꢁ 12:1ðc1:00; MeOHÞ. 1H NMR (300 MHz, CD3COCD3) d 3.00
(dd, J = 13.5 Hz, 9.0 Hz, 1H), 3.17 (dd, J = 13.5 Hz, 5.4 Hz, 1H), 3.67
(s, 3H), 4.49 (dd, J = 9.0 Hz, 5.4 Hz, 1H), 5.01 (s, 2H), 6.65 (d,
J = 9.0 Hz, 1H), 7.14 (s, 2H), 7.24–7.37 (m, 7H), 7.04–7.17 (m, 4H),
7.80 (d, J = 7.8 Hz, 2H). Anal. Calcd for C18H2010BNO6: C, 60.67; H,
5.66; N, 3.93. Found: C, 60.26; H, 6.03; N, 3.97.
a
3.3. N -Benzyloxycarbonyl-3-iodo-
L
-alanine methyl ester (6)
3.6. p-(10B)Borono-
L-phenylalanine (1)
To a solution of I2 (62.9 g, 248 mmol) and imidazole (16.9 g, 248
mmol) in CH2Cl2 (300 mL) was added PPh3 (65.0 g, 248 mmol) por-
tionwise, and the solution was stirred for 30 min at 0 °C. After stir-
ring for 1 h at room temperature, to the reaction mixture was
added the solution of 5 (31.5 g, 124 mmol) in CH2Cl2 (300 mL)
dropwise, and the mixture was stirred for 5 h. The reaction mixture
A suspension of 8 (1.90 g, 5.33 mmol) in 3 M HCl (200 mL) was
stirred for 17 h at 80 °C. The reaction mixture was washed with
Et2O (70 mL ꢀ 3), and concentrated in vacuo. The residue was dis-
solved in iPrOH (50 mL), and to the solution was added propylene
oxide (621 mg, 10.7 mmol). After stirring for 14 h, the reaction
mixture was concentrated in vacuo. The crystalline residue was

4980
Y. Hattori et al. / Tetrahedron Letters 49 (2008) 4977–4980
6. Kumanishi, A.; Ozaki, N.; Tanimori, S.; Tshuda, T.; Takagaki, M.; Ono, K.;
Kirihata, M. KURRI-KR 2000, 54, 315.
recrystallized from water to give 1 as colorless crystals (922 mg,
83.1%): mp 285–298 °C (decomp.). ½a D25
ꢂ
ꢁ5:2ðc0:50; 1M HClÞ. 1H
7. Natural boron consists of two stable isotopes viz. 10B and 11B with the
abundance of 18.8 at. % and 81.2 at. %, respectively.
NMR (300 MHz, D2O) d 2.97 (ddd, J = 18.2 Hz, 14.4 Hz, 5.4 Hz,
2H), 3.80 (dd, J = 14.4 Hz, 5.4 Hz, 1H), 7.15 (d, J = 7.8 Hz, 2H), 7.55
(d, J = 7.8 Hz, 2H). Anal. Calcd for C9H1210BNO4ꢃ0.5H2O: C, 49.76;
H, 6.03; N, 6.45. Found: C, 49.90; H, 6.27; N, 6.23.
8. Nakao, H.; Morimoto, T.; Kirihata, M. Biosci. Biotech. Biochem. 1996, 60, 683.
9. Nakamura, H.; Masaru, F.; Yamamoto, Y. Bull. Chem. Soc. Jpn. 2000, 73, 231.
10. Malan, C.; Morin, C. Synlett 1996, 167.
11. Noguchi, H.; Hojo, K.; Suginome, M. J. Am. Chem. Soc. 2007, 129, 758.
12. Trost, M. B.; Rudd, T. M. Org. Lett. 2003, 5, 4599.
13. Hwang, D. R.; Helquist, P.; Shekhani, M. S. J. Org. Chem. 1985, 50, 1264.
14. Tabanella, S.; Valancogne, I.; Jackson, F. W. R. Org. Biomol. Chem. 2003, 1, 4245.
15. The method previously reported by Kirihata and co-workers8 gives
L
- Bpa from
References and notes
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