Synthesis of (2S)-2-amino-3-(2′,6′-dibromo-4′-hydroxy)phenylpropionic acid (2,6-dibromo-L-tyrosine)

Abstract

(2S)-2-Amino-3-(2′,6′-dibromo-4′-hydroxy)phenylpropionic acid (2,6-dibromo-L-tyrosine) 1a has been synthesized by two methods. The first is by enantioselective hydrolysis of the N-trifluoroacetyl derivative of the racemic 2,6-dibromotyrosine with carboxypeptidase A. The kinetic parameters of activity of carboxypeptidase A against N-trifluoroacetyl-2,6-dibromo-L-tyrosine have also been estimated (V_max, 0.32 mM min^–1 mg^–1; K_m 16.15 mM). The second is an asymmetric synthesis by Schöllkopf’s bis-lactim ether method. Alkylation of the lithiated bis-lactim ether of cyclo(-D-Val-Gly) 6 with 2,6-dibromo-4-methoxybenzyl bromide and subsequent hydrolysis with aqueous trifluoroacetic acid gives 2,6-dibromo-4-methoxy-L-tyrosine methyl ester 8. Demethylation of the ester 8 with boron tribromide affords the amino acid 1a. The enantiomeric purity of 2,6-dibromo-L-tyrosine 1a obtained by both methods has been determined by HPLC with a chiral stationary column and is found to be more than 95% (ee).