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 therapy 1 (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 molecules 2–8 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) investigations 10 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- benzene 17 as shown in Scheme 1. The 3-substituted 0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2005.04.130 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. Tetrahedron Letters 46 (2005) 4915–4917 Tetrahedron Letters