Issue in Honor of Prof. M. Makosza ARKIVOC 2004 (iii) 11-21
tumor cell sufficient for the therapy. However, BPA and BSH are not ideal, since higher concentrations of boron are desirable. Consequently, the synthesis of BPA analogues, including boronated natural and unnatural amino acids and amino alcohols, is the subject of active research.15-21 Recently, it was shown that amino acids, such as 1-aminocycloalkanoic acids, cross the blood brain barrier and localize in Glioblastoma Multiforme and metastatic malignant melanoma more avidly than BPA.22 This observation prompted a search for BPA analogues and other boronic acids containing 1-aminocycloalkanecarboxylic acid moiety.17-21 Such boronated cyclic amino acids contain a quaternary carbon atom bonded to the amino acid functionality. It seemed interesting to compare the effect of such quaternary center incorporated in an acyclic moiety of BPA analogue with a representative cycloalkyl analogue as potential boron carriers for BNCT. Consequently, we decided to prepare 2-amino-2-methyl-3-(4-dihydroxyborylphenyl)propionic acid (3, a-methyl-BPA), the simplest BPA analogue containing a quaternary center, and for comparison its cycloalkyl analogue, 1-amino-3-(4-dihydroxyborylbenzyl)cyclobutanecarboxylic acid 4, (Figure 1).
B(OH)2 H2N CH3 COOH B(OH)2 NH2 COOH SH Na2 = BH; = BB(OH)2 COOHH2N 1 2 3 4 BPA BSH a-methyl-BPA Figure 1
Results and Discussion
a-Methyl-BPA was prepared following two routes, from 4-allylbromobenzene 6 via hydantoin, and from D,L-alanine by deprotonation-benzylation. 1-(4-Bromophenyl)propan-2-one 9, a convenient intermediate for the first route, was prepared starting from 1,4-dibromobenzene 5 in an overall 70% yield and >99% purity. Lower yield than might be expected results from competing formation of 1,4-diallylbenzene 7 in the first step, leading to a mixture of 5-7. To suppress the formation of 7, 4-bromophenylmagnesium bromide was prepared from 5 by the addition of reagents in a reversed order, and the amount of 7 decreased to 10-15%. Both products have very close boiling points and their separation by distillation is inconvenient. Consequently, a mixture of 6 and 7, 86:14, was used for the oxymercuration-demercuration reaction. The product alcohol 8 was cleanly separated from the product diol by distillation, and was oxidized
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