SYNTHESIS OF N-EPSILON-(P-BROMOPHENYL)-L-LYSINE AND N-TAU-(P-BROMOPHENYL)-L-HISTIDINE AS MODELS FOR ADDUCTS OF BROMOBENZENE 3,4-OXIDE TO PROTEIN - OBSERVATION OF AN UNUSUAL PD-CATALYZED N-TAU-ARYL TO N-PI-ARYLSUBSTITUENT MIGRATION

Bromobenzene 3,4-oxide (1), the putative toxic metabolite of bromobenz ene, is known to alkylate protein sulfur nucleophiles in vivo and is p ostulated to alkylate protein nitrogen nucleophiles, the expected prod ucts of which would include, after hydrolysis, N(t)au-(p-bromophenyl)- L-histidine (8) and N(e)psilon- (p-bromophenyl)-L-lysine (7). These no n-proteinogenic amino acids have now been synthesized by unambiguous r outes and their stability under protein hydrolysis conditions demonstr ated. Treatment of N-alpha-Cbz-lysine with sodium nitroprusside gave t he epsilon-lysinol derivative, which by successive treatment with CBr4 /Ph(3)P and excess p-bromoaniline and deprotection (6.0 M HCl, 110 deg rees C) afforded an overall 14% yield of 7. Alkylation of N alpha-Ac-L -histidine methyl ester with p-fluoronitrobenzene, followed by reducti on, a modified Sandmeyer bromo-dediazotization (tert-BuONO/CuBr2), and deprotection afforded 8 in 10% overall yield. An unexpected N(t)au- t o N(p)i-aryl migration was observed during hydrogenation of a N(t)au-( p-nitrophenyl)histidine derivative over Pd/charcoal; it was avoided by use of SnCl2/ethanol for nitro reduction. The N alpha-acetyl derivati ves of 7 and 8, of interest as haptens for use in raising antibodies a gainst proteins alkylated by epoxide 1, were also prepared and charact erized.