Synthesis of a Potential Boron Neutron Capture Therapy Agent: 1-Amino-cyclobutane-1-carboxylic Acid Bearing a Butylboronic Acid Side Chain

Article abstract of DOI:10.1055/s-2003-42479

A novel boronated aminocyclobutanecarboxylic acid was synthesized for potential use in neutron capture therapy. The synthesis involves the preparation of tosylate 5, which was then converted to an amino acid using Bucherer-Strecker methodology. The molecu

Full text of DOI:10.1055/s-2003-42479

2890
SPECIAL TOPIC
Synthesis of a Potential Boron Neutron Capture Therapy Agent: 1-Amino-
cyclobutane-1-carboxylic Acid Bearing a Butylboronic Acid Side Chain
Synthesis of
a
Pote
e
ntial Boron
o
N
eutron Ca
r
pture
T
h
g
erapy
A
gente W. Kabalka,* Min-Liang Yao
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, TN 37996-1600, USA
Fax +1(865)9742997; E-mail: kabalka@utk.edu
Received 15 October 2003
ACBC derivatives were prepared previously. In a contin-
uation of our studies, we have now synthesized a novel
butylboronic substituted amino acid 1 (Figure 1).
Abstract: A novel boronated aminocyclobutanecarboxylic acid
was synthesized for potential use in neutron capture therapy. The
synthesis involves the preparation of tosylate 5, which was then
converted to an amino acid using Bucherer–Strecker methodology.
The molecule was modeled after the unnatural amino acid, 1-ami-
nocyclobutane-1-carboxylic acid, which has shown high uptake in
brain tumors.
CO2H
(HO)2B(CH2)4
NH2
1
Key Words: amino acids, neutron capture therapy, boronic acid,
synthesis, cyclobutanecarboxylic acid
Figure 1 Structure of amino acid 1
The synthesis of 1 is initiated utilizing 3-benzyloxymeth-
ylcyclobutanone (2) (Scheme 1). The reaction of 2 with
hexane-1,2-diol produces the corresponding ketal 3 in
high yield.16 The choice of the diol is critical to the syn-
thetic strategy.17 Not only is the hexanediol ketal less vol-
atile and easier to handle than the ethanediol ketal but it is
more stable in the subsequent deprotection reaction. Since
ketal 3 exists in the spiro configuration and contains two
chiral centers, diasteromers are formed. The ratio of dias-
teromers is essentially 1:1. In the 13C NMR spectrum of
ketal 3, the resonances of the carbons at the spiro core are
clearly differentiated. The spectral differences are also ap-
parent in 4, 5 and 6. The hydrogenation of ketal 3 (10%
Pd/C) proceeds smoothly in methanol at room tempera-
ture and produces 4 after simple filtration and removal of
solvent. Treatment of 4 with p-toluenesulfonyl chloride at
0 °C, followed by slow warming to room temperature,18
affords tosylate 5 in moderate yield (65%). Significant
quantities (28% based on alcohol 4) of chloride 5b are
also formed. Chlorination of in situ generated tosylate is a
common side reaction in tosylate preparations.19 We dis-
covered that the formation of 5b can be completely elim-
inated by keeping the reaction temperature at 0 °C which
increased the yield of 5 to 94%.
Boron neutron capture therapy1 (BNCT) is dependent on
the selective deposition of 10B in tumor cells. Irradiation
by thermal neutrons then results in a fission reaction,
which releases highly energetic particles that destroy the
cells. To date, a variety of molecules have been used to de-
liver boron to tumor cells. These include carbohydrates,2
polyamines,3 amino acids,4 nucleosides,5 antisense
agents,6 porphyrins,7 and peptides.8 In recent years, en-
couraging results have been obtained using 4-dihydroxy-
borylphenylalanine (BPA) as the tumor specific
boronated agent.9
It is believed that the amino acids are preferentially taken
up by growing tumor cells. Positron emission tomography
(PET) investigations10 carried out at The University of
Tennessee using carbon-11 labeled 1-aminocyclobutane-
1-carboxylic acid (ACBC) demonstrated that this amino
acid localizes in tumors more avidly than BPA. Very re-
cently, Goodman reported that 18F labeled 1-amino-3-
(fluoromethyl)cyclobutanecarboxylic acid also localizes
in tumors.11
Prompted by the hypothesis that incorporation of bond ro-
tation restriction in bioactive peptides can augment the
biopotency, selectivity and metabolic stability,12 the syn-
thesis of conformationally restricted 1-aminocyclobu-
tane-1-carboxylic acids has attracted much attention in
recent years.13 Encouraging results have been report-
ed.12,13a For example, the introduction of a 3-(aminometh-
yl)- or 3-(hydroxymethyl)aminocyclobutanecarboxylic
acid into the antitumor peptide Tuftsin significantly in-
creased resistance to enzymatic hydrolysis.
C4H9
C4H9
O
O
O
O
O
BnO
HO
BnO
2
4
3
C4H9
C4H9
+
O
O
O
O
Cl
TsO
5
5b
We have focused our efforts on the synthesis of boronated
ACBC derivatives. Carborane14 and phenylboronic acid15
Scheme 1 Reagents and conditions: (a) hexane-1,2-diol, PTSA,
benzene, reflux; (b) H2, 10% Pd/C, MeOH, r.t.; (c) TsCl, pyridine,
0 °C
SYNTHESIS 2003, No. 18, pp 2890–2893
x
x.
x
x
.
2
0
0
3
Advanced online publication: 12.11.2003
DOI: 10.1055/s-2003-42479; Art ID: C14103SS
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Synthesis of a Potential Boron Neutron Capture Therapy Agent
2891
deuterated solvents. Microanalyses were performed by Atlantic Mi-
crolab, Inc. Norcross, Georgia. HRMS-FAB (M + 1) spectra were
obtained on a ZABEQ instrument in a glycerol matrix.
Tosylate 5 couples smoothly with allylmagnesium chlo-
ride to give alkene 6 in 89% isolated yield.20 In the 13C
NMR spectrum of alkene 6, four distinct resonances are
visible for the two secondary cyclobutyl carbon atoms.
The ketal group in 6 is removed using dilute hydrochloric
acid in refluxing ethanol, which generates 7. Ketone 7 is a
highly volatile compound. Hydantoin 8 is prepared by re-
action of 7 with potassium cyanide and ammonium car-
bonate in an Ace pressure tube at 60 °C for 8 hours (83%
yield).21 Hydantoin 8 is obtained in a 2.5:1 ratio of stereo-
isomers with the cis-isomer being the main product. The
observed selectivity can be attributed to the steric interac-
tion of the 3-butene substitutent during the formation of
3-Benzyloxymethylcyclobutanone Ketal (3)
A 250 mL, three-necked, round-bottomed flask equipped with a
Dean–Stark apparatus and a reflux condenser was charged with 2
(7.6 g, 40 mmol), hexane-1,2-diol (6.2 g, 44 mmol), and p-toluene-
sulfonic acid (500 mg) in benzene (150 mL). The reaction mixture
was refluxed at 120 °C (oil bath) for 14 h and the progress of the re-
action was monitored by TLC. After 14 h, the flask was cooled to
r.t., and sat. aq NaHCO3 (20 mL) was added. The mixture was trans-
ferred to a separatory funnel, washed sequentially with H2O (15
mL) and then brine (15 mL), dried (MgSO4), and concentrated un-
der reduced pressure to give a colorless oil. The product was puri-
the hydantoin, i.e. during the addition of cyanide to the fied by column chromatography (hexane–EtOAc, 20:1) to yield
imino species.22 The hydroboration of 9 is accomplished
11.2 g (97%) of 3 as a colorless liquid.
1H NMR (250 MHz, CDCl3/TMS): = 7.25–7.41 (m, 5 H), 4.50 (s,
2 H), 3.90–4.02 (m, 2 H), 3.48 (d, J = 6.26 Hz, 2 H), 3.42 (dd,
J = 12.3, 6.7 Hz, 1 H), 2.18–2.46 (m, 3 H), 2.05–2.17 (m, 2 H),
1.17–1.65 (m, 6 H), 0.90 (t, J = 6.49 Hz, 3 H).
13C NMR (62.89 MHz, CDCl3/TMS): = 138.4, 128.2, 127.5,
106.8, 106.7, 75.8, 75.5, 74.2, 72.8, 68.9, 68.6, 39.1, 38.7, 33.3,
33.0, 27.8, 24.7, 24.5, 22.6, 14.0.
using
3
equivalents of diisopinocampheylborane
(Ipc2BH) in THF at room temperature.23 The hydrolysis of
10 in the presence of hydrochloric acid (12 M) produces 1
in good yield (Scheme 2).
C4H9-n
C4H9-n
O
O
O
O
b
a
MS: m/z = 290 (M+), 169, 142, 100, 91.
TsO
5
6
Anal. Calcd for C18H26O3 (290.41): C, 74.45, H, 9.02. Found: C,
74.23; H, 9.08.
O
3-Hydroxymethylcyclobutanone Ketal (4)
NH
c
d,e,f
O
To a 100 mL round-bottomed flask fitted with a septum cap, ketal 3
(11.2 g, 38.6 mmol), 10% Pd/C (1.12 g), and MeOH (60 mL) were
added. The air in the flask was removed under vacuum and H2 was
introduced using a H2-filled balloon. After stirring for 24 h at r.t.,
the reaction mixture was filtered and the residual Pd/C was washed
with MeOH. Concentration of the filtrate and washings under re-
duced pressure yielded the colorless product 4 (7.6 g, 99%).
N
O
7
H
8
O
NH
g
(HO)2B
N
9
O
H
1H NMR (250 MHz, CDCl3/TMS): = 3.93–4.05 (m, 2 H), 3.63 (d,
J = 6.18 Hz, 2 H), 3.45 (dd, J = 12.4, 6.7 Hz, 1 H), 3.68 (s, 1 H),
2.23–2.47 (m, 3 H), 2.00–2.17 (m, 2 H), 1.16–1.64 (m, 6 H), 0.91 (t,
J = 6.48 Hz, 3 H).
CO2H
NH2
(HO)2B
1
13C NMR (62.89 MHz, CDCl3/TMS): = 106.7, 106.5, 75.9, 75.7,
69.0, 68.8, 66.7, 66.6, 38.6, 38.5, 38.3, 33.3, 33.1, 27.8, 26.8, 26.6,
22.6, 13.9.
Scheme 2 Reagents and conditions: (a) allylmagnesium chloride,
THF, r.t. to reflux; (b) 2 M HCl, EtOH, reflux; (c) (NH4)2CO3, KCN,
EtOH–H2O, 60 °C; (d) (Ipc)2BH, THF, 0 °C to r.t.; (e) MeCHO, THF,
0 °C to r.t.; (f) 2 M HCl, r.t.; (g) 12 M HCl, 150 °C
HRMS: m/z calcd for C11H20O3 + 1: 201.1491; found: 201.1490.
Anal. Calcd for C11H20O3 (200.28): C, 65.97; H, 10.07. Found: C,
65.44; H, 10.09.
In conclusion, we have reported an eight-step synthesis of
a novel 1-aminocyclobutane-1-carboxylic acid containing
an alkylboronic acid substituent. The new agent is cur-
rently being evaluated as a BNCT agent.
Tosylate 5
A chilled solution of ketal 4 (7.4 g, 37 mmol) in pyridine (10 mL)
was added via syringe to a solution of tosyl chloride (7.73 g, 40.7
mmol) in anhyd pyridine (10 mL) maintained at 0 °C. After stirring
at 0 °C for 18 h under N2, the reaction mixture was diluted with
chilled Et2O (50 mL), washed with aq CuSO4 (3 × 20 mL), brine
(20 mL), dried (MgSO4), and concentrated in vacuo. The residual
product was purified by column chromatography (hexane–EtOAc,
4:1) to yield a colorless liquid 5 (12.3 g, 94%).
1H NMR (250 MHz, CDCl3/TMS): = 7.78 (d, J = 8.20 Hz, 2 H),
7.34 (d, J = 8.20 Hz, 2 H), 4.04 (d, J = 5.79 Hz, 2 H), 3.84–4.03 (m,
2 H), 3.36–3.42 (m, 1 H), 2.45 (s, 3 H), 2.06–2.42 (m, 3 H), 1.94–
2.04 (m, 2 H), 1.22–1.58 (m, 6 H), 0.90 (t, J = 6.79 Hz, 3 H).
3-Benzyloxymethylcyclobutanone (2) was prepared according to
the literature procedure.24 All reagents were used as received. Et2O
and THF were distilled from sodium benzophenone ketyl. Column
chromatography was performed using silica gel (grade 60, 230–400
mesh, ICN Biomedicals GmbH, Eschwege, Germany). Analytical
TLC was performed on 250 m silica gel (Analtech, Inc., Newark,
DE) and was visualized by phosphomolybdic acid, PdCl2, and
AgNO3 solutions.
1H NMR and 13C NMR spectra were recorded at 250.13 and 62.89
MHz, respectively. In cases where more than one isomer formed,
we have reported the 13C NMR spectrum of the major isomer.
Chemical shifts for 1H NMR and 13C NMR spectra were referenced
to TMS and measured with respect to the residual protons in the
13C NMR (62.89 MHz, CDCl3/TMS): = 144.6, 133.0, 129.7,
127.8, 106.0, 105.0, 76.0, 75.7, 73.5, 69.0, 68.7, 38.7, 38.5, 38.3,
33.0, 32.9, 27.7, 23.9, 23.8, 22.6, 21.5, 13.9.
Synthesis 2003, No. 18, 2890–2893 © Thieme Stuttgart · New York

2892
G. W. Kabalka, M.-L. Yao
SPECIAL TOPIC
MS: m/z = 355 (M + 1), 281, 176, 142, 100.
Hydantoin 8
A 25 mL Ace pressure tube was charged with 7 (0.62 g, 5.0 mmol),
aq EtOH (50%, 12.0 mL), KCN (650 mg, 10 mmol), and
(NH4)2CO3 (2.4 g, 25 mmol). The reaction vessel was sealed and
heated at 60 °C (oil bath) for 8 h. A faint yellow precipitate formed.
The reaction mixture was cooled to r.t. and the vessel carefully
opened in a fume hood. The mixture was concentrated under re-
duced pressure and the solid obtained was purified by column chro-
matography (hexane–EtOAc,1:2) to afford 8 as a white solid (0.81
g, 83%).
1H NMR (CD3OD/TMS): = 5.65–5.81 (m, 1 H), 4.78–4.97 (m, 2
H), 2.47–2.55 (m, 2 H), 2.20–2.32 (m, 2 H), 1.84–1.98 (m, 3 H),
1.41–1.56 (m, 2 H).
13C NMR (62.89 MHz, CD3OD/TMS): = 181.1, 158.5, 139.5,
115.1, 60.0, 39.6, 37.6, 32.4, 27.6.
Anal. Calcd for C18H26O5S (354.47): C, 60.99; H, 7.39. Found: C,
60.98; H, 7.47.
When the reaction was carried out at r.t., 5b was isolated as a by-
product.
5b
1H NMR (250 MHz, CDCl3/TMS): = 3.93–4.04 (m, 2 H), 3.60 (d,
J = 6.63 Hz, 2 H), 2.42–3.48 (m, 1 H), 2.40–2.53 (m, 3 H), 2.06–
2.19 (m, 2 H), 1.28–1.62 (m, 6 H), 0.91 (t, J = 6.78 Hz, 3 H).
13C NMR (62.89 MHz, CDCl3/TMS):: = 105.8, 105.7, 76.0, 75.7,
69.0, 68.8, 49.1, 40.1, 40.0, 39.8, 33.2, 33.0, 27.8, 27.4, 27.3, 22.6,
13.8.
Anal. Calcd for C11H19ClO2 (218.72): C, 60.40; H, 8.76. Found: C,
60.38; H, 8.59.
Anal. Calcd for C10H14N2O2: C, 61.84; H, 7.27; N, 14.42. Found: C,
61.83; H, 7.29; N, 14.13.
Alkene 6
A 250 mL, two-necked flask fitted with a reflux condenser, a mag-
netic stir bar, and a septum was flushed with N2 and charged with 5
(10.6 g, 30 mmol) dissolved in anhyd THF (20 mL) at 0 °C. Allyl-
magnesium chloride (150 mmol, 75 mL of a 2 M solution in THF)
was added drop-wise via syringe over a 30 min period. The stirring
was continued at 0 °C for an additional 30 min, at which time the
cooling bath was removed and the mixture was refluxed for 8 h. The
mixture was stirred overnight at r.t., and then quenched with concd
aq NH4Cl (30 mL) and Et2O (50 mL). Following the separation of
the organic phase, the aqueous phase was extracted with Et2O
(3 × 30 mL), the combined organic phases were washed with brine
(2 × 20 mL), and dried (MgSO4). The crude product was purified
by column chromatography (hexane–EtOAc, 50:1) to yield 6 as a
colorless oil (5.98 g, 89%).
1H NMR (250 MHz, CDCl3/TMS): = 5.65–5.77 (m, 1 H), 4.83–
4.95 (m, 2 H), 3.84–3.95 (m, 2 H), 3.35–3.41 (m, 1 H), 2.27–2.39
(m, 2 H), 1.78–1.98 (m, 5 H), 1.18–1.56 (m, 8 H), 0.83 (t, J = 6.62
Hz, 3 H).
13C NMR (62.89 MHz, CDCl3/TMS): = 138.5, 114.4, 106.7,
106.6, 75.8, 75.4, 69.0, 68.5, 41.8, 41.7, 41.6, 41.4, 35.7, 35.6, 33.5,
33.0, 32.0, 27.8, 24.8, 24.6, 22.6, 13.9.
Boronohydantoin 9
Diisopinocampheylborane (Ipc)2BH was prepared according to the
literature procedure.23 A 100 mL round-bottomed flask was fitted
with a septum, a magnetic stirring bar, and connected to a N2 bub-
bler. The flask was flushed with N2 and held at a positive static pres-
sure of N2. BH3·THF (50 mmol, 50 mL, 1.0 M) was added slowly
and the mixture stirred at 0 °C for 1 h. The reaction was left at 0 °C
for 3 d to give the required crystalline product. Compound 8 (0.63
g, 3 mmol) was placed in a 150 mL round-bottomed flask and dis-
solved in THF (15 mL) at 0 °C. (Ipc)2BH (9 mmol) in THF (20 mL)
was added drop-wise via a syringe. The mixture was allowed to
warm to r.t. and stirred for 16 h. Freshly distilled acetaldehyde (12
mmol) was added and the mixture stirred for an additional 12 h. Ex-
cess acetaldehyde was removed under vacuum and the mixture was
hydrolyzed with aq HCl (5 mL, 2 M). The mixture was extracted
with EtOAc (3 × 30 mL) and the combined organic phases were
dried (MgSO4). The solvent was removed under reduced pressure
and the residue purified by column chromatography (MeOH) to af-
ford 9 as a white solid (0.65 g, 85%).
1H NMR (DMSO-d6/TMS): = 8.52 (s, 1 H), 7.42 (s, 1 H), 2.47–
2.58 (m, 2 H), 2.17–2.31 (m, 3 H), 1.04–1.48 (m, 6 H), 0.62 (t,
J = 7.75 Hz, 2 H).
MS: m/z = 224 (M+), 209, 100, 82.
13C NMR (62.89 MHz, DMSO-d6/TMS): = 178.8, 155.9, 57.6,
38.3, 36.5, 29.5, 26.3, 24.1.
Anal. Calcd for C14H24O2 (224.35): C, 74.95; H, 10.78. Found: C,
74.99, H, 10.85.
HRMS-FAB: m/z calcd for C13H22BN2O5 (M + H + gly – 2H2O; ob-
tained in a glycerol matrix): 297.1624; found: 297.1618.
3-(But-3-enyl)cyclobutanone (7) (Caution! Highly Volatile)
A 100 mL, round-bottomed flask was charged with 6 (5.6 g, 25
mmol) dissolved in EtOH (150 mL) and aq 2 M HCl (5 mL). The
mixture was refluxed overnight at which time the TLC indicated
complete disappearance of the starting ketal. After cooling to r.t.,
the mixture was extracted with Et2O (3 × 50 mL), the combined or-
ganic phases were dried (MgSO4), and the solvent was removed by
distillation. The residue was purified using silica gel chromatogra-
phy (pentane–Et2O, 30:1). The ketone 7 was obtained as a colorless
liquid (2.79 g, 90%).
1H NMR (250 MHz, CDCl3/TMS): = 5.74–5.91 (m, 1 H), 4.97–
5.08 (m, 2 H), 3.07–3.20 (m, 2 H), 2.65–2.74 (m, 2 H), 2.35–2.43
(m, 1 H), 2.11 (dd, J = 7.70, 6.86 Hz, 2 H), 1.69 (dd, J = 7.69, 6.86
Hz, 2 H).
1-Amino-3-[4-(dihydroxyboryl)butyl]cyclobutanecarboxylic
Acid (1)
Boronohydantoin 9 (446 mg, 1.5 mmol) was placed in a 25 mL Ace
pressure tube along with 12 M HCl (4 mL). The tube was sealed and
heated to 150 °C (oil bath) for 40 min. It was then cooled to r.t.,
carefully opened (Hood!), charcoal was added, and the mixture fil-
tered through a pad of Celite. The Celite pad was washed with H2O.
Removal of the H2O under reduced pressure gave a white solid (260
mg, 81%).
1H NMR (D2O/TMS): = 3.46–3.49 (m, 2 H), 2.47–2.68 (m, 2 H),
2.21–2.40 (m, 3 H), 1.09–1.43 (m, 6 H) 0.67 (m, 2 H).
13C NMR (62.89 MHz, D2O/TMS): = 180.2, 60.4, 42.3, 41.0, 34.9,
34.0, 29.6, 24.2.
13C NMR (62.89 MHz, CDCl3/TMS): = 208.7, 137.6, 115.1, 52.5,
35.5, 32.5, 23.4.
MS: m/z = 123 (M+ – 1), 109, 80, 67.
HRMS: m/z calcd for C12H23BNO5 (M + H + gly – 2H2O; obtained
in a glycerol matrix): 272.1672; found: 272.1679.
Anal. Calcd for C8H12O (124.18): C, 77.38; H, 9.74. Found: C,
77.29; H, 9.65.
Synthesis 2003, No. 18, 2890–2893 © Thieme Stuttgart · New York

SPECIAL TOPIC
Acknowledgment
Synthesis of a Potential Boron Neutron Capture Therapy Agent
(8) (a) Ivanov, D.; Bachovchin, W. W.; Redfield, A. G.
2893
Biochemistry 2002, 41, 1587. (b) Leush, A.; Jungblut, L.;
Moroder, L. Synthesis 1994, 305.
The authors wish to thank the U. S. Department of Energy and the
Robert H. Cole Foundation for support of this research.
(9) (a) Barth, R. F.; Yang, W.; Bartus, R. T.; Rotaru, J. H.;
Ferketich, A. K.; Moeschberger, M. L.; Nawrocky, M. M.;
Coderre, J. A.; Rofstad, E. K. Int. J. Radiat. Oncol. Biol.
Phys. 2002, 52, 858. (b) Kiger, W. S. III; Palmer, M. R.;
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2001, 155, 611. (c) Mallesch, J. L.; Moore, D. E.; Allen, B.
J.; McCarthy, W. H.; Jones, R.; Stening, W. A. Int. J. Radiat.
Oncol. Biol. Phys. 1994, 28, 1183.
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