Large-Scale Syntheses of FMOC-Protected Non-Proteogenic Amino Acids: Useful Building Blocks for Combinatorial Libraries

Abstract

Convenient and reliable large-scale procedures for the protection of various amino acids with N-(9-fluorenylmethoxycarbonyl)oxysuccinimide (FMOC-OSu) are described. Commercially available 4-aminomethylbenzoic acid and trans-4-(aminomethyl)cyclohexanecarboxylic acid were converted into their corresponding FMOC-derivatives in excellent yields without the need for an extractive workup. In addition, FMOC-cis-β-amino acids were also prepared, employing a [2 + 2]-cycloaddition strategy between a cyclic olefin and N-chlorosulfonyl isocyanate (CSI). The resulting N-chlorosulfonyl β-lactams were reduced to the parent β-lactams with sodium sulfite and then converted to the cis-β-amino acid hydrochlorides by exposure to aqueous hydrochloric acid. The resulting cis-β-amino acids were converted to their FMOC-derivatives under conditions similar to those developed for the commercially available amino acids. Differences in the conditions employed between these β-amino acids and the commercial derivatives were observed, primarily in the nature of the base required for the reaction. A possible rationale for the differences in behavior is described. These FMOC-amino acid derivatives are valuable intermediates for the solid-phase synthesis of combinatorial libraries.