Catalytic asymmetric synthesis of α-methyl-p-boronophenylalanine

Shingo Harada; Ryota Kajihara; Risa Muramoto; Promsuk Jutabha; Naohiko Anzai; Tetsuhiro Nemoto

doi:10.1016/j.bmcl.2018.03.075

Catalytic asymmetric synthesis of α-methyl-p-boronophenylalanine

Bioorg Med Chem Lett. 2018 Jun 1;28(10):1915-1918. doi: 10.1016/j.bmcl.2018.03.075. Epub 2018 Mar 28.

Authors

Shingo Harada¹, Ryota Kajihara², Risa Muramoto², Promsuk Jutabha³, Naohiko Anzai⁴, Tetsuhiro Nemoto⁵

Affiliations

¹ Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan. Electronic address: Sharada@chiba-u.jp.
² Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan.
³ School of Medicine, Dokkyo Medical University, 880, Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, Japan.
⁴ School of Medicine, Dokkyo Medical University, 880, Kitakobayashi, Mibu, Shimotsuga, Tochigi 321-0293, Japan; Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8670, Japan; Molecular Chirality Research Center, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan.
⁵ Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 260-8675, Japan; Molecular Chirality Research Center, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan. Electronic address: tnemoto@faculty.chiba-u.jp.

PMID: 29655983
DOI: 10.1016/j.bmcl.2018.03.075

Abstract

p-Boronophenylalanine (l-BPA) is applied in clinical settings as a boron carrier for boron neutron capture therapy (BNCT) to cure malignant melanomas. Structural modification or derivatization of l-BPA, however, to improve its uptake efficiency into tumor cells has scarcely been investigated. We successfully synthesized (S)-2-amino-3-(4-boronophenyl)-2-methylpropanoic acid in enantioenriched form as a novel candidate molecule for BNCT. Key steps to enhance the efficiency of this synthesis were enantioselective alkylation of N-protected alanine tert-butyl ester with a Maruoka catalyst and Miyaura borylation reaction to install the boron functionality.

Keywords: BNCT; BPA; Drug delivery; Miyaura borylation; Phase transfer catalysis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkylation
Boron Compounds / chemical synthesis
Boron Compounds / chemistry*
Catalysis
Coordination Complexes / chemistry
Palladium / chemistry
Phenylalanine / analogs & derivatives*
Phenylalanine / chemical synthesis
Phenylalanine / chemistry
Stereoisomerism

Substances

Boron Compounds
Coordination Complexes
Phenylalanine
Palladium
4-boronophenylalanine