Catalytic asymmetric synthesis of α-methyl-p-boronophenylalanine

Article abstract of DOI:10.1016/j.bmcl.2018.03.075

p-Boronophenylalanine (L-BPA) is applied in clinical settings as a boron carrier for boron neutron capture therapy (BNCT) to cure malignant melanomas. Structural modification or derivatization of L-BPA, however, to improve its uptake efficiency into tumor cells has scarcely been investigated. We successfully synthesized (S)-2-amino-3-(4-boronophenyl)-2-methylpropanoic acid in enantioenriched form as a novel candidate molecule for BNCT. Key steps to enhance the efficiency of this synthesis were enantioselective alkylation of N-protected alanine tert-butyl ester with a Maruoka catalyst and Miyaura borylation reaction to install the boron functionality.

Full text of DOI:10.1016/j.bmcl.2018.03.075

Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Catalytic asymmetric synthesis of a-methyl-p-boronophenylalanine
a
a
b
b,c,d
Shingo Harada a, , Ryota Kajihara , Risa Muramoto , Promsuk Jutabha , Naohiko Anzai
,
⇑
Tetsuhiro Nemoto a,d,
⇑
a Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan
b School of Medicine, Dokkyo Medical University, 880, Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, Japan
c Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan
d Molecular Chirality Research Center, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263–8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
p-Boronophenylalanine (
L-BPA) is applied in clinical settings as a boron carrier for boron neutron capture
Received 28 December 2017
Revised 23 March 2018
Accepted 27 March 2018
Available online xxxx
therapy (BNCT) to cure malignant melanomas. Structural modification or derivatization of
L
-BPA, how-
ever, to improve its uptake efficiency into tumor cells has scarcely been investigated. We successfully
synthesized (S)-2-amino-3-(4-boronophenyl)-2-methylpropanoic acid in enantioenriched form as a
novel candidate molecule for BNCT. Key steps to enhance the efficiency of this synthesis were
enantioselective alkylation of N-protected alanine tert-butyl ester with
Miyaura borylation reaction to install the boron functionality.
a Maruoka catalyst and
Keywords:
BNCT
BPA
Ó 2018 Elsevier Ltd. All rights reserved.
Drug delivery
Phase transfer catalysis
Miyaura borylation
Introduction
ment of the uptake efficiency to malignant tumor cells have hardly
been investigated.5 Recently, we reported that
L
-BPA was trans-
ported to human pancreatic cancer cells, MIA PaCa-2 and T3M4
by a -type amino acid transporter 1 (LAT1), whereas quite low
amounts of
-BPA was transported to the cells.6 On the other hand,
quaternarization of -amino acids confers increased stability
BNCT is a biologically targeted radiotherapy for malignancy
based on nuclear capture and fission reactions that occur when
non-radioactive 10B is irradiated with low energy thermal neu-
trons.1 BNCT in combination with surgery is attracting growing
attention for the treatment of patients with high-grade gliomas.
L
D
a
against metabolic degradation and influences the conformational
To sustain a lethal 10B(n, )7Li reaction for successful treatment,
a
rigidity and lipophilicity.7 These backgrounds led us to hypothesize
an adequate amount of 10B must be selectively delivered to all
that the chemical modification of
L-BPA into the corresponding
tumor cells (ca. 109 atoms/cell or ca. 20
lg/g weight), and a suffi-
quaternary -amino acid derivative would be worth trying to eval-
a
cient number of thermal neutrons must be absorbed by the 10B
atoms. Thus, the efficiency of BNCT relies on the selective delivery
of boron carriers to malignant cells.
uate the uptake efficiency.
In the present article, we report a concise methodology for the
synthesis of (S)-a a
-methyl-boronophenylalanine8 possessing
Sodium mercaptoundecahydro-closo-dodecaborate (BSH) and
tetra-substituted carbon center in an enantioenriched form as a
(S)-p-boronophenylalanine (
as boron delivery agents for BNCT (Fig. 1).2 In recent years, consid-
erable attention was focused on -BPA due to its uptake efficiency
into tumor cell.
L-BPA) have been clinically explored
novel candidate boron delivery agent for BNCT. A phase-transfer
catalyzed asymmetric alkylation for the synthesis of chiral
a,a-dia-
L
lkyl- -amino acid analogues and Miyaura borylation reaction to
a
L
-BPA has been used as a boron carrier to cure
introduce the boron functionality were efficiently utilized as key
steps to obtain the BPA derivative.
malignant melanomas3 and evaluated for BNCT clinical trials of
glioblastoma multiforme and melanoma.4 Analogues of BPA based
on modifications of the molecular structure, however, for improve-
Results and discussion
Our study commenced with the asymmetric alkylation of
N-protected alanine tert-butyl ester 1 under phase-transfer cataly-
sis,9 which is a powerful strategy for the synthesis of optically
⇑
Corresponding authors at: Graduate School of Pharmaceutical Sciences, Chiba
University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan (T. Nemoto).
E-mail addresses: Sharada@chiba-u.jp (S. Harada), tnemoto@faculty.chiba-u.jp
(T. Nemoto).
active
a-amino acid equivalents (Table 1). First, widely available
https://doi.org/10.1016/j.bmcl.2018.03.075
0960-894X/Ó 2018 Elsevier Ltd. All rights reserved.
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2
S. Harada et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
yield with poor enantioselectivity (25% ee, entry 1). Other cinchona
alkaloid-based organocatalysts (4 and 5) produced similar results
(entries 1 vs 2, 3). Next, binaphthyl-modified chiral phase-transfer
catalyst11 (R)-6, called a ‘‘simplified Maruoka catalyst”,12 was
applied to the reaction with 80% aqueous cesium hydroxide at 0
°C, furnishing (S)-2 in 60% yield with excellent enantioselectivity
of 96% ee, even with low catalyst loading (1 mol%, entry 4). Efforts
to directly introduce a boron motif by reactions with 8 under var-
ious conditions were unsuccessful (entries 5–8). While a higher
reaction temperature decreased the enantioselectivity, the use of
a larger amount of 7 improved the yield to 82% (entries 9, 10). Fur-
ther lower catalyst loading resulted in decreased enantioselectivity
(entry 12), and therefore the reaction conditions of entry 10 were
determined to be optimum for producing (S)-2 in an enantioen-
riched form. A larger scale reaction was also feasible without any
problem (entry 11).13 An optical antipode of (R)-6 is also commer-
cially available, and therefore synthetic procedures for both enan-
tiomers of 2 were established.
Fig. 1. Currently used boron carriers for BNCT.
cinchona alkaloids10 were tested based on the following protocol. A
reaction of 1 with p-bromobenzyl bromide 7 and 10 equivalents of
KOH/K2CO3 in dichloromethane on a 0.2-mmol scale was per-
formed in the presence of 10 mol% catalyst 3 at room temperature
for 18 h, followed by treatment with aqueous citric acid for hydrol-
ysis of the imine moiety, providing alkylated product (S)-2 in 66%
Table 1
Optimization of the reaction conditions for phase-transfer catalyzed asymmetric alkylation.a
Entry
Cat.
X (mol%)
Alkyl bromide
Solvent
Temp
Yield (%)
% ee (config.)
1a
2a
3a
4
5
6
7
8
9
3
4
5
10
10
10
1
1
1
1
1
1
1
7 (1.1 eq)
7 (1.1 eq)
7 (1.1 eq)
7 (1.2 eq)
8 (1.2 eq)
8 (1.2 eq)
8 (1.2 eq)
8 (1.2 eq)
7 (1.2 eq)
7 (3.0 eq)
7 (3.0 eq)
7 (3.0 eq)
CH2Cl2
CH2Cl2
CH2Cl2
rt
rt
rt
66
79
72
60
0
0
0
0
76
82
89
85
25 (S)
32 (S)
34 (R)
96 (S)
–
–
–
–
60 (S)
97 (S)
97 (S)
85 (S)
(R)-6
(R)-6
(R)-6
(R)-6
(R)-6
(R)-6
(R)-6
(R)-6
(R)-6
Toluene
Toluene
Toluene
Toluene
MeCN
Toluene
Toluene
Toluene
Toluene
0 °C
0 °C
60 °C
Reflux
0 °C
rt
0 °C
0 °C
0 °C
10
11b
12
1
0.5
a
10 equivalents of KOH and K2CO3 were used as bases.
Reaction was performed on 2.2-mmol scale.
b
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S. Harada et al. / Bioorganic & Medicinal Chemistry Letters xxx (2018) xxx–xxx
3
Table 2
Optimization of the reaction conditions for Miyaura borylation reaction.
Entry
Pd cat
Ligand
Base
Solvent
Temp (°C)
(S)-10 yield
Recovered SM
1
2
3
4
PdCl2(dppf)
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
–
KOAc
KOAc
KOAc
Et3N
KOAc
KOAc
DMSO
DMSO
Dioxane
Dioxane
Dioxane
DMF
80
80
80
80
65
80
17%
Trace
42%
15%
20%
75%
61%
56%
None
27%
None
None
XPhos
XPhos
XPhos
XPhos
XPhos
5
6a
a
The reaction was performed for 6 h. dppf is 1,10-bis(diphenylphosphino)ferrocene. XPhos is 2-dicyclohexylphosphino-20,40,60-triisopropylbiphenyl.
introduce the aryl boronic acid pinacol ester motif were used as
key steps. To elucidate the pharmacological profile, we are cur-
rently performing a transport assay of (S)-11 and its enantiomer
into a human pancreatic cancer cell through LAT1 and the results
will be reported in due course.
ð1Þ
Acknowledgments
This work was supported by JSPS KAKENHI Grant Numbers
JP16K18840 and 15K07850, Strategic Research Foundation Grant-
aided Project for Private Universities (S1412001) (N.A.), and Cancer
Research Funds for Patients and Family by Medical and Welfare
Network Chiba (N.A.).
With the key amino acid derivative (S)-9 possessing a tetra-sub-
stituted carbon center in hand after N-protection of (S)-2 with
Boc2O/Et3N (Eq. (1)), the introduction of a boron functionality into
the arene unit of (S)-9 was examined using a Miyaura borylation
reaction14,15 with Pd catalysis (Table 2). First, standard conditions
were applied utilizing PdCl2(dppf) complex (5 mol%) in the pres-
ence of bis(pinacolato)diboron (2 equiv) and KOAc in DMSO sol-
vent at 80 °C for 2 days, giving the desired (S)-10, but in only
17% yield (entry 1). While the change from dppf to XPhos as a mon-
odentate ligand did not improve the yield (entry 2), the use of diox-
ane as a solvent was effective (42% yield, entry 3). Lowering the
temperature or the use of an organobase (Et3N) did not produce
satisfactory results (entries 4 and 5). Finally, conducting the bory-
lation in DMF solvent increased the yield to 75% (entry 6).
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.bmcl.2018.03.075.
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4
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