Fmoc Amino Acid Fluorides: Convenient Reagents for the Solid-Phase Assembly of Peptides Incorporating Sterically Hindered Residues

Article abstract of DOI:10.1021/jo00091a011

Fmoc amino acid fluorides, recently shown to be a new class of rapid-acting acylating agents in peptide synthesis are well suited for the solid-phase synthesis of medium-sized peptides such as ACP(65-74), magainin-II-amide, and h-CRF.The most important advantage of these reagents is their high reactivity in the coupling of sterically hindered amino acid residues, such as α-aminoisobutyric acid (Aib), results which are at least partly due to the small size of the fluoride leaving group.Both h-(Aib^32-35)-CRF(1-41), bearing four consecutive Aib-residues, and alamethicin acid, neither previously accessible by solid-phase synthesis, were successfully synthesized via acid fluorides using unusually short coupling times.In contrast, attempted syntheses via UNCA's and PyBroP activation, both reported to be well suited for sterically hindered systems, failed to give the desired peptides.These remarkable differences prompted a more detailed comparison of the acid fluorides with symmetric anhydrides, UNCA's, and the PyBroP activation technique.Side products formed during the acylation of hindered amino components by Fmoc-Aib-NCA were identified and their formation rationalized.These side products could have their origin in the demonstrated instability of Fmoc-NCA's in the presence of tertiary bases or in a diversion of the position of attack on the NCA from the more hindered to the less-hindered carbonyl function by a bulky nucleophile.Clearly caution is required when such bases are employed to enhance coupling rates for hindered systems.