A Concise Synthesis of Enantiomerically Pure L-(4-Boronophenyl)Alanine from L-Tyrosine

Abstract

4-Boronophenylalanine (BPA)1 is a practical boron compound, which is clinically used not only for the treatment of malignant melanoma but also for that of brain tumor, on neutron capture therapy (NCT).1–3 Since Mishima and co-workers4 revealed that the L-form of BPA is more efficiently incorporated into melanoma cells than racemic one, the enantioselective synthesis of L-BPA has been required. Enriched L-BPA was prepared enzymatically through α-chymotrypsin hydrolysis5 of the ethyl ester of racemic BPA synthesized by the traditional method.1,6 In this case, 50% of another enantiomer (D-BPA) was recovered from the racemic material. Recently, two synthetic routes of L-BPA were reported. Asymmetric hydrogenation route gave L-BPA with enantiomeric excess of up to 88% (96% ee after recrystallization).7 Another route using palladium-catalyzed coupling reaction of iodophenylboronate with the chiral organozinc derived from L-serine needed rather lengthy synthetic steps.8 Herein we report a concise synthesis of enantiomerically pure L-BPA from L-tyrosine using palladium-catalyzed carbon-boron bond formation reaction (eq. 1).