Synthesis of a boronated amino acid as a potential neutron therapy agent: 1-Amino-3-[(dihydroxyboryl)ethyl]-cyclobutanecarboxylic acid

Article abstract of DOI:10.1016/j.tetlet.2005.04.130

A novel boronated aminocyclobutanecarboxylic acid was synthesized in 10 steps for potential use in neutron capture therapy. The molecule was modeled after the unnatural amino acid 1-aminocyclobutanecarboxylic acid, which has shown high uptake in brain tumors.

Full text of DOI:10.1016/j.tetlet.2005.04.130

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4915–4917
Synthesis of a boronated amino acid as a potential neutron therapy
agent: 1-amino-3-[(dihydroxyboryl)ethyl]-
cyclobutanecarboxylic acid
George W. Kabalka,* Min-Liang Yao and Abhijit Navarane
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, TN 37996-1600, USA
Received 5 April 2005; revised 26 April 2005; accepted 27 April 2005
Available online 4 June 2005
Abstract—A novel boronated aminocyclobutanecarboxylic acid was synthesized in 10 steps for potential use in neutron capture
therapy. The molecule was modeled after the unnatural amino acid 1-aminocyclobutanecarboxylic acid, which has shown high
uptake in brain tumors.
Ó 2005 Elsevier Ltd. All rights reserved.
Boron neutron capture therapy1 (BNCT) is a cancer
treatment that involves the irradiation of tumors con-
taining boron-10 with low-energy neutrons. The result-
ing excited boron-11 nucleus then undergoes a prompt
fission and releases high energy a-particles and lith-
ium-7 ions. The linear energy transfer (LET) of these
heavy charged particles has a range of approximately
one cell diameter, thus they are only lethal to the cells
in which they are generated. The clinical success of
BNCT depends on two factors: (1) selective delivery of
a sufficient quantity of nontoxic boron-10 containing
compounds to the tumor and (2) a neutron flux suffi-
cient to achieve the prerequisite nuclear reaction. BNCT
is an attractive modality for the treatment of patients
with high-grade gliomas and metastatic brain tumors
whose life expectancy is generally less than 1 year
despite aggressive treatments using surgery, and radio-
and chemotherapy. To date, a variety of molecules2–8
have been used to deliver boron to tumor cells. Encour-
aging results have been obtained using 4-dihydroxy-
borylphenylalanine (BPA) and sodium mercaptoun-
decahydrododecaborate (BSH) as the tumor specific
boronated agent, and both are being used in clinical
trials.9
It is believed that amino acids are preferentially taken
up by growing tumor cells. Positron emission tomogra-
phy (PET) investigations10 using carbon-11 labeled
1-aminocyclobutanecarboxylic acid (ACBC) demon-
strated that this amino acid localizes in tumors more
avidly than BPA. Recently, Goodman reported that
fluorine-18 labeled 1-amino-3-(fluoromethyl)cyclo-
butanecarboxylic acid and its derivatives also localize
in tumors.11 Prompted by the hypothesis that incorpora-
tion of bond rotation restriction in bioactive peptides
can augment biopotency, selectivity and metabolic sta-
bility,12 the synthesis of conformationally restricted
1-aminocyclobutane-1-carboxylic acids (ACBCs) has
attracted attention in recent years.13
We have focused our efforts on the synthesis of boro-
nated ACBC derivatives.14,15 Two novel 3-butylboronic
and 3-methylboronic substituted ACBC derivatives were
synthesized for in vivo biodistribution evaluation.16 To
complete a structure–activity relationship study (by
adjusting the lipophilicity of the compounds), we pre-
pared a 3-ethylboronic substituted ACBC 1 (Fig. 1).
The synthesis of 1 starts from but-3-enyloxymethyl-
benzene17 as shown in Scheme 1. The 3-substituted
Keywords: Boronic acid; Amine borane; Amino acid; Cyclobutane
derivative.
*
Corresponding author. Tel.: +1 865 974 3260; fax: +1 865 974
2997; e-mail: kabalka@utk.edu
Figure 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.130

4916
G. W. Kabalka et al. / Tetrahedron Letters 46 (2005) 4915–4917
Scheme 1. Reagents and conditions: (a) Cl3CCOCl, POCl3, Zn–Cu, Et2O, reflux; (b) Zn, HOAc, 0 °C to reflux; (c) 1,2-hexanediol, PTSA, benzene,
reflux; (d) H2, Pd/C (10%), MeOH, rt; (e) CBr4, PPh3, CH2Cl2, rt; (f) NaOH (6 M), PEG-600, 90 °C; (g) HCl (2 M), EtOH, reflux; (h) (NH4)2CO3,
KCN, EtOH/H2O (1:1), 60 °C; (i) (Ipc)2BH, THF, 0 °C to rt; (j) CH3CHO, THF, 0 °C to rt; (k) HCl (2 M), rt; (l) HCl (12 M), 160 °C.
cyclobutanone skeleton was constructed by a [2+2]
cycloaddition reaction. Cyclobutanone 2 was obtained
by the cycloaddition of but-3-enyloxymethylbenzene
with dichloroketene, which was generated in situ from
trichloroacetyl chloride in the presence of a zinc–copper
couple and phosphorous oxychloride. Cyclobutanone 2
is unstable during silica gel column chromatography
and the crude product was used directly in the next step.
The reductive dechlorination of 2 with zinc in acetic
acid18 produced cyclobutanone 3 in 64% isolated yield
(two steps).
anol, generating 8. To avoid the loss of the highly vola-
tile 8, crude 8 was used directly for the Bucherer–
¨
Strecker reaction. Crude 8, potassium cyanide and
ammonium carbonate were sealed in an Ace pressure
tube and heated at 60 °C for 9 h. The reaction produced
hydantoin 9 in 83% isolated yield (two steps). Hydan-
toin 9 is formed in a 2.5:1 ratio of stereoisomers with
the cis-isomer being the main product. The hydrobora-
tion of
9 was accomplished using 3.0 equiv of
diisopinocampheylborane (Ipc2BH) in THF at room
temperature. The resultant diisocampheylborane prod-
uct was readily converted to boronic acid 10 by reaction
with acetaldehyde and then aqueous HCl according to
the literature procedure.22 Hydrolysis of 10 in the pres-
ence of hydrochloric acid (12 M) produced 1 in good
yield.23 This new agent is currently being evaluated as
a BNCT agent.
In our previous work,19 we found that cyclobutanone
ethanediol ketals are somewhat unstable compared to
the corresponding 1,2-hexanediol derivatives, which
led us to prepare 3. Another advantage of using 1,2-hex-
anediol is that intermediates 6 and 7 are less volatile.
Since ketal 4 is a spiro compound and contains two
stereogenic centers, diasteromers (in a 1:1 ratio) are
formed. In the 13C NMR spectrum of ketal 4, the reso-
nances of the carbons at the spiro core are clearly differ-
entiated. These spectral differences are also apparent in
intermediates 5 and 6. Hydrogenation of ketal 4 (10%
palladium on charcoal) in methanol at room
temperature gave 5 in quantitative yield.
Acknowledgements
The authors wish to thank the US Department of
Energy and the Robert H. Cole Foundation for sup-
port of this research.
Bromination of 5 using CBr4/PPh3 in dichloromethane20
at room temperature produced 3-(bromoethyl)cyclobu-
tanone acetal, 6, in 94% isolated yield. The dehydrobro-
mination of 6 to generate the alkenyl group was realized
using NaOH in PEG-600.21 The ketal group in 7 was
removed using dilute hydrochloric acid in refluxing eth-
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