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 , 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 a-aminoisobutyric acid (Aib), results which are at least partly due to the small size of the fluoride leaving group. Both h-(Aib32-35)-CRF(l-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.
A sequence-and conformation-dependent, unexpected high extent of aspartimide and piperidide formation is observed for the synthesis of Asp(0But)-containing peptides using piperidine in the Fmoc-chemistry.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.