Synthesis of novel boron containing unnatural cyclic amino acids as potential therapeutic agents

Article abstract of DOI:10.1016/S0040-4039(01)01486-1

Two boronated α-amino acids, 1-amino-3-boronocyclopentanecarboxylic acid and 1-amino-3-boronocycloheptanecarboxylic acid were prepared. The key step in the syntheses was the 1,4-boration of the α,β-unsaturated cyclic ketones using the bis-pinacolatodiboron ester to generate the boronated ketones which were then converted to the corresponding amino acids.

Full text of DOI:10.1016/S0040-4039(01)01486-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7145–7146
Synthesis of novel boron containing unnatural cyclic amino acids
as potential therapeutic agents
George W. Kabalka,* Bhaskar C. Das and Sasmita Das
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, TN 37996-1600, USA
Received 3 May 2001; accepted 7 August 2001
Abstract—Two boronated a-amino acids, 1-amino-3-boronocyclopentanecarboxylic acid and 1-amino-3-boronocycloheptanecar-
boxylic acid were prepared. The key step in the syntheses was the 1,4-boration of the a,b-unsaturated cyclic ketones using the
bis-pinacolatodiboron ester to generate the boronated ketones which were then converted to the corresponding amino acids.
© 2001 Elsevier Science Ltd. All rights reserved.
In the last decade, there has been considerable interest
in boron neutron capture therapy (BNCT),1 a binary
approach to the treatment of cancer in which a com-
pound containing boron-10 is selectively delivered to
tumor tissues prior to irradiation by neutrons.2 The
interaction of a boron-10 atom with a thermal neutron
produces an a-particle and a high energy lithium-7 ion.
The linear energy transfer (LET) of these heavily
charged particles have a range of approximately one
cell diameter. To minimize damage to normal tissues,
the quantity of boron in the tumor (ꢀ30 mg of 10B per
gram of tumor) must exceed that in the surrounding
normal tissue by at least a factor of three.3,4 The clinical
success of BNCT depends on two factors: effective
delivery of a sufficient quantity of boron to the targeted
tumor and a neutron flux sufficient to achieve the
prerequisite nuclear reaction while minimizing damage
to healthy tissue. Early BNCT clinical trials were disap-
pointing in that they failed to achieve either of these
goals.5 However, significant advances in the modifica-
tion of the nuclear reactors and tumor seeking selective
boron containing pharmaceuticals have been made in
recent years.6
fluorine-18 labeled BPA and carbon-11 labeled 1-
aminocyclobutanecarboxylic acid revealed that cyclic
amino acids localize in GBM and MM tumors more
avidly than BPA.8 For this reason, we have focused our
efforts on cyclic a-amino acids such as 1-aminocyclo-
butanecarboxylic acid (ACBC) as the boron carrier. We
reported the syntheses of a meta-carborane containing
ACBC derivative, a less liphophilic nido-analogue,9 and
O
O
a
b
O
n
B
n
O
5 (n = 1)
6 (n = 3)
3 (n = 1)
4 (n = 3)
H
O
N
NH2
CO2H
B
N
H
O
c
O
It is believed that amino acids are preferentially taken
up by growing tumor cells. Clinical trials are now
underway for the treatment of both Glioblastoma Mul-
tiforme (GBM)7 and metastatic malignant melanoma
(MM) utilizing a boron-containing amino acid, para-
boronophenylalanine (BPA). Recent positron emission
tomography (PET) investigations carried out at the
University of Tennessee on BNCT patients using
n
B
O
OH
n
OH
1 (n = 1)
2 (n = 3)
7 (n = 1)
8 (n = 3)
Scheme 1. Reaction conditions: (a) (i) CuCl, LiCl, KOAc,
bis-pinacolatodiboron, DMF, N2 atm.; (ii) H2O (b) KCN,
(NH4)2CO3, EtOH:H2O (1:1), 80°C; (c) 10 M HCl, 150°C, 15 h.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01486-1

7146
G. W. Kabalka et al. / Tetrahedron Letters 42 (2001) 7145–7146
a solubilized meta-carborane derivative.10 It is known
that 1-aminocycloalkanecarboxylic acids cross the
blood brain barrier (BBB).11 We now wish to report the
synthesis of a boronated aminocyclopentanecarboxylic
acid 1, and the more lipophilic seven-membered ring
analogue 2.
6. (a) Nakagawa, Y.; Hatanaka, H. J. Neurooncol. 1997, 33,
105–115; (b) Soloway, A. H.; Tjarke, W.; Barnum, B. A.;
Rong, F. G.; Barth, R. F.; Codogni, I. M.; Wilson, J. G.
Chem. Rev. 1998, 98, 1515–1562.
7. Coderre, J.; Rubin, P.; Freedman, J. A.; Hensen, T. J.;
Wooding, T. S.; Joel, D.; Gash, D. Intl. J. Rad. Oncol.,
Biol. Phys. 1994, 28, 1067–1077.
8. Hubner, K. F.; Thie, J. A.; Smith, G. T.; Kabalka, G.
W.; Keller, I. B.; Cliefoth, A. B.; Campbell, S. K.;
Buonocore, E. Clin. Positron Imaging 1998, 1, 165.
9. (a) Srivastava, R. R.; Singhaus, R.; Kabalka, G. W. J.
Org. Chem. 1997, 62, 4476–4478; (b) Srivastava, R. R.;
Singhaus, R.; Kabalka, G. W. J. Org. Chem. 1997, 62,
8730–8734; (c) Srivastava, R. R.; Singhaus, R.; Kabalka,
G. W. J. Org. Chem. 1999, 64, 8495–8500.
10. (a) Das, B. C.; Kabalka, G. W.; Srivastava, R. R.; Bao,
W.; Das, S.; Li, G. J. Organomet. Chem. 2000, 614–615,
255–261; (b) Das, B. C.; Das, S.; Li, G.; Bao, W.;
Kabalka, G. W. Synlett. 2001, 1419.
NH2
CO2H
NH2
CO2H
OH
B
OH
B
OH
OH
1
2
The key synthetic step in the formation of the title
compounds is the preparation of ketones 5 and 6
(Scheme 1) via addition of a diboron reagent to the
corresponding a,b-unsaturated carbonyl compounds.12
We were able to prepare compounds 5 and 6 via the
boronation of cyclic alkenones 3 and 4 using bis-pina-
colatodiboron in DMF.13 Compound 5 was isolated in
70% yield while the yield of compound 6 was 82%.
Compound 5 is thick liquid while compound 6 is a low
melting solid. The corresponding ketones were allowed
to react with ammonium carbonate and potassium cya-
nide in an Ace pressure tube at 80°C for 5 h.14 The
hydantoins 7 and 8 were formed in good yields. (The
yield of 7 was 90% and the yield of 8 was 95%.) It is
noteworthy that the hydantoins were difficult to
hydrolyze. If milder conditions or shorter reaction
times were employed, only the pinacol ester was
hydrolyzed not the hydantoin.15
11. Aoyagi, M.; Agranoff, G. W.; Washburn, L. C.; Smith,
O. R. J. Neurochem. 1988, 50, 1220–1226.
12. (a) Ishiyama, T.; Miyaura, N. J. Synth. Org. Chem. 1999,
57, 503; (b) Ito, H.; Yamanaka, H.; Tateiwa, J.-I.;
Hosomi, A. Tetrahedron Lett. 2000, 41, 6821–6825.
13. Hydantoin 7 (0.14 g, 0.50 mmol) was placed in a 15 mL
Ace pressure tube along with concentrated HCl (5 mL, 10
M). The tube was sealed and heated to 150°C (oil bath)
for 15 h. It was then cooled to room temperature, care-
fully opened (Hood!), charcoal added, and the mixture
passed through Celite. The Celite pad was washed succes-
sively with water. The filtrate and washes were combined
and the water removed in vacuo to yield a diastereomeric
mixture of 1 (0.079 g, 73%) as the solid hydrochloride:
Rf=0.71 (isopropanol:water:acetic acid; 1.0:1.0:0.5); solid
turns brown at 256°C without melting; (major
diastereomer) 1H NMR (D2O): l 1.19–2.09 (broad m).
13C NMR (D20): l 178.7, 67.2, 39.5, 34.63, 34.0, 26.1; 11B
NMR (D2O): l 31.8; HR-FAB-MS (M+H+gly-2H2O;
obtained in a glycerol matrix), calcd for C9HHH17BNO5:
230.120, found 230.137.
Acknowledgements
The authors wish to thank the US Department of
Energy and the Robert H. Cole Foundation for support
of this Research.
14. Hydantoin 8 (0.15 g, 0.50 mmol) was placed in a 15 mL
Ace pressure tube along with concentrated HCl (5 mL, 10
M), and the reaction carried out as described for 7 (Ref.
13) to obtain a diastereomeric mixture of 2 (0.084 g, 72%)
as the solid hydrochloride: Rf=0.65 (isopropanol:water:
acetic acid; 1.0:1.0:0.5); solid turns brown at 248°C with-
out melting; (major diastereomer) 1H NMR (D2O): l
1.23–2.12 (broad m). 13C NMR (D20): l 177.6, 66.1, 38.0,
37.1, 34.6, 33.3, 32.6, 24.6; 11B NMR (D2O): l 30.9;
HR-FAB-MS (M+H+gly-2H2O; obtained in a glycerol
matrix), calcd for C11HHH21BNO5: 258.151, found
258.151.
References
1. Barth, R. F.; Soloway, A. H.; Brugger, R. M.; Fairchild,
R. G. Cancer 1992, 70, 2995–3007.
2. Barth, R. F.; Soloway, A. H.; Goodman, J. H.; Grah-
bauer, R. A.; Greha, N.; Blue, T. E.; Yang, W.; Tjarks,
W. Neurosurgery 1999, 44, 433–450.
3. Fairchild, R. G.; Bond, V. P. Int. J. Radiat. Oncol. Biol.
Phys. 1985, 11, 831–835.
4. Zamenhof, R. G.; Kalend, A. M.; Bloomer, W. J. Natl.
Cancer Inst. 1992, 84, 84–75, 1290–1291.
15. Alonso, F.; Milo, I.; Najera, C.; Sansano, J. M.; Yus, M.
Tetrahedron 1995, 51, 10259–10280.
5. Sweet, W. H. J. Neuroncol. 1997, 33, 19–26.