Nucleophilic enantioselective synthesis of 6-[ 18F]Fluoro- l-dopa via two chiral auxiliaries

Abstract

Asymmetric nucleophilic synthesis of 6-[ 18F]fluoro- l-dopa was investigated in order to reach an enantiomeric excess of close to 100% of the l form of this amino acid. The radiochemical synthesis required [ 18F]fluoride as fluorinating agent and regioselective nucleophilic substitution of commercially available 6-nitroveratraldehyde. The [ 18F]fluorobenzaldehyde thus obtained was easily converted to the corresponding 2-[ 18F]fluoro-4,5-dimethoxybenzyl bromide. This alkylating agent was added to the lithium enolates of 1-(S)-(−)camphor imine of t-butyl glycinate ( 1) and (S)-(−)-1-Boc-2-t-butyl-3-methyl-4-imidazolidinone [(S)- Boc-BMI] ( 2) in order to compare the enantiomeric excess of the l form obtained in each case with these two chiral inductors. The l-isomer of fluorodopa was isolated after H1 hydrolysis and HPLC purification in 5–10% radiochemical yield (decay corrected). The overall synthesis time was of 110 min. Through this synthetic pathway, the l-isomer of fluorodopa was obtained in 83% e.e with 1 and 96% e.e with 2 respectively, as determined by chiral HPLC. A practical three step preparative scale synthesis of 6-[ 19F]fluoro- d,l-dopa is also presented.