An Efficient Synthesis of p-Boronophenylalanine and Its Homologues by the Reaction of Ethyl Isocyanoacetate with a p-Formylbenzeneboronic Acid Derivative

Abstract

p-Boronophenylalanine (BPA) and its related compounds are worthwhile synthetic targets due to their proven and potential biological activities, particularly with respect to the boron-neutron capture therapy (BNCT) for metastatic melanomas and other tumors. The first synthesis of BPA was achieved by the alkylation of diethyl aminoacetomalonate with p-bromomethylbenzeneboronic acid and subsequent hydrolysis; however, the overall yield was not satisfactory.¹⁾ On the other hand, we have developed efficint synthetic routes of nonproteinous amino acids which possess specific functional groups on their side chain using ethyl isocyanoacetate as a synthon.²⁾ These results prompt us to explore a more convenient and practical synthetic route to BPA and its homologues. In this paper, we describe a simple and efficient synthesis of D,L-BPA and p-boronophenylserine (BPS), a new analogue of BPA, via the short routes shown in the schemes.