Synthesis of (2S)-2-(9H-9-fluorenylmethoxycarbonylamino)-3-(9-phenanthrenyl) propionic acid

Abstract

The synthesis of (2S)-2-(9H-9-fluorenylmethoxycarbonylamino)-3-(9-phenanthreyl) propionic acid was completed in 8 steps, which gave the target molecule in 35% overall yield from phenanthrene-9-carboxaldehyde. The racemic (R/S)-amino acid was prepared from diethyl acetamidomalonate and 9-(bromomethyl) phenanthrene by a modification of the Sorensen method. The esterification of this amino acid afforded amino acid ester, which was later resolved into its optically active form, (2S)-2-acetylamino-3-(9-phenanthrenyl) propionic acid, by enzymatic hydrolysis of the ester group with subtilisin CLECs-BL. The enzymatic resolution gave (S)-amino acid in 45% conversion (>98%ee) after incubation in mixed acetone-aqueous phosphate buffer (pH 7.5-8.0) at 37-40ํC for 24 hours. An enatiomeric excess (ee) of resolved product was obtained from 1H NMR spectrum of MTPA derivative of resolved amino acid. The acetyl group of the resolved amino acid was replaced with 9H-9-fluorenylmethoxycarbony1-(Fmoc-) protecting group for further peptide synthesis.