FMOC AMINO-ACID FLUORIDES - CONVENIENT REAGENTS FOR THE SOLID-PHASE ASSEMBLY OF PEPTIDES INCORPORATING STERICALLY HINDERED RESIDUES

Fmoc amino acid fluorides, recently shown to be a new class of rapid-a cting acylating agents in peptide synthesis are well suited for the so lid-phase synthesis of medium-sized peptides such as ACP(65-74), magai nin-II-amide, and h-CRF. The most important advantage of these reagent s is their high reactivity in the coupling of sterically hindered amin o acid residues, such as cu-aminoisobutyric acid (Aib), results which are at least partly due to the small size of the fluoride leaving grou p. Both h-(Aib(32-35))-CRF(1-41),bearing four consecutive Aib-residues , and alamethicin acid, neither previously accessible by solid-phase s ynthesis, were successfully synthesized via acid fluorides using unusu ally 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 remarkab le differences prompted a more detailed comparison of the acid fluorid es with symmetric anhydrides, UNCA's, and the PyBroP activation techni que. Side products formed during the acylation of hindered amino compo nents by Fmoc-Aib-NCA were identified and their formation rationalized . These side products could have their origin in the demonstrated inst ability of Fmoc-NCA's in the presence of tertiary bases or in a divers ion of the position of attack on the NCA from the more hindered to the less-hindered carbonyl function by a bulky nucleophile. Clearly cauti on is required when such bases are employed to enhance coupling rates for hindered systems.