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

Abstract

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.

Synthesis and Conformational Analysis of Pentapeptides Containing Enantiomerically Pure 2,2‐Disubstituted Glycines

“…This interaction can be described by the graph set motif [21] of S (10). N(1)-H forms an intermolecular H-bond with the carboxylic acid carbonyl O-atom of a neighboring molecule, thereby linking the molecules into extended chains, which run parallel to the [0 1 0] direction and which can be described by the graph set motif of C (11). N(4)-H forms an intermolecular H-bond with the amide O-atom of a neighboring molecule, thereby linking the molecules into extended chains, which run parallel to the [1 0 0] direction and which can be described by the graph set motif of C(5).…”

N-Acylation in combinatorial chemistry

“…Compounds 41 can be advantageously prepared from Fmoc-, Boc-, or Cbz-amino acids via cyanuric fluoride, and are often in crystalline form. 90 Fmoc-amino acid fluorides were also applied to solid-phase peptide synthesis using sterically hindered amino acids, 91 and for the acylation of sulfonamide type linkers (Scheme 19). Kim reported on 2-methyl-2-thiazoline (42), 93 designed to be a good leaving group for Nacylation; in competitive acylation of a primary and secondary amine, N-acyl-2-methylamino-2-thiazolines (43) gave higher yields of the products with primary amines, in high chemoselectivity as compared to using acid chlorides and anhydrides (Scheme 20).…”

Synthesis of 1,1-Dioxobenzo[b]thiophene-2-ylmethyloxycarbonyl (Bsmoc) Protected N-Methyl Amino Acids by Reduction of Bsmoc-5-Oxazolidinones and Their Use in Peptide Synthesis

“…Acid fluorides have been shown to accomplish difficult esterifications such as between a weakly nucleophilic secondary alcohol and a cyclohexyl amino acid, where other methods of activation such as DCC/DMAP, mixed anhydride, BOP-Cl or BOP have failed [22]. Successful synthesis of acyl carrier protein 65-74 fragment (ACP), magainin-II-amide, human corticotropin-releasing factor (h-CRF) and peptide related to Alzheimers disease A (1-42) which are known as difficult sequences to synthesize, have been accomplished efficiently employing acid fluorides [23]. Very difficult sequence containing sterically hindered C -dialkylamino acids such as Aib [24], 1-aminocyclohexane-1-carboxylic acid and 4-amino-piperidine-4-carboxylic acid [25] have also been achieved with greater efficiency by the use of corresponding acid fluorides.…”