Large-scale syntheses of FMOC-protected non-proteogenic amino acids: Useful building blocks for combinatorial libraries

Convenient and reliable large-scale procedures for the protection of variou s amino acids with N-(9-fluorenyimethoxycarbonyl)oxysuccinimide (FMOC-OSu) are described. Commercially available 4-aminomethylbenzoic acid and trans-4 -(aminomethyl)cyclohexanecarboxylic acid were converted into their correspo nding FMOC-derivatives in excellent yields without the need for an extracti ve workup. In addition, FMOC-cis-beta -amino acids were also prepared, empl oying a [2 + 2]-cycloaddition strategy between a cyclic olefin and N-chloro sulfonyl isocyanate (CSI). The resulting N-chlorosulfonyl fl-lactams were r educed to the parent beta -lactams with sodium sulfite and then converted t o the cis-fi-amino acid hydrochlorides by exposure to aqueous hydrochloric acid. The resulting cis-fi-amino acids were converted to their FMOC-derivat ives under conditions similar to those developed for the commercially avail able amino acids. Differences in the conditions employed between these beta -amino acids and the commercial derivatives were observed, primarily in th e nature of the base required for the reaction. A possible rationale for th e differences in behavior is described. These FMOC-amino acid derivatives a re valuable intermediates for the solid-phase synthesis of combinatorial li braries.