Synthesis, conformational analysis, and spectroscopic characterization of peptides based on Daf, the first rigid transition‐metal receptor, cyclic C^α,α‐disubstituted glycine

Abstract

Three series of terminally protected model oligopeptides to the nonamer level, based on 9-amino-4,5-diazafluorene-9-carboxylic acid, the first rigid bipyridine-type C(alpha,alpha)-disubstituted glycine, and either Gly, L-Ala, or Aib residues were synthesized by solution methods and fully characterized. The molecular structures of two derivatives and one tripeptide were determined in the crystal state by x-ray diffraction. Moreover, the solution preferred conformations of these peptides were assessed by Fourier transform infrared absorption and (1)H-NMR techniques. A comparison with the known structural tendencies of the strictly related C(alpha,alpha)-disubstituted glycyl residues 1-aminocyclopentane-1-carboxylic acid and 9-aminofluorene-9-carboxylic acid is made, and the implications for the use of the 9-amino-4,5-diazafluorene-9-carboxylic acid residue in conformationally constrained analogs of bioactive peptides are briefly examined. A spectroscopic (uv absorption, fluorescence, CD) characterization of this novel heteroaromatic C(alpha,alpha)-disubstituted glycine is also reported. Finally, preliminary conformational data and membrane activity measurements are discussed for an analog of the lipopeptaibol antibiotic [L-Leu(11)-OMe] trichogin GA IV in which a 9-amino-4,5-diazafluorene-9-carboxylic acid residue was synthetically incorporated in position 1 (replacing the original Aib residue).

Control of peptide conformation by the Thorpe-Ingold effect (C?-tetrasubstitution)

“…The onset of a folded structure by Hms(Ipr) (O,O‐isopropylidene‐C α ‐hydroxymethylserine) (Figure 8) containing compounds may be prevented by (peptide) N i +1 H … O (side‐chain ether) intramolecular H‐bonds, thus favoring the fully extended conformation (Figure 11). 134 The related Afc (9‐amino‐9‐fluorenecarboxylic acid)135–137 and Daf (9‐amino‐4,5‐diazafluorene‐9‐carboxylic acid)138 residues (Figure 8), by virtue of their central five‐membered ring (as in Ac 5 c) and the two aromatic moieties directly linked to the α‐carbon (as in DΦg), may adopt either the turn/helical or the fully extended conformation. The fully extended conformation of these residues is more frequently observed in amino acid derivatives and very short peptides.…”

Recent progress on the stereoselective synthesis of cyclic quaternary α-amino acids

“…Apart from these classical rings, the conformational tendencies of other cyclic amino acids such as Hms(Ipr) or O , O -isopropylidene-α-hydroxymethylserine,25 Afc or 9-amino-9-fluorenecarboxylic acid,26,27 Daf or 9-amino-4,5-diazafluorene-9-carboxylic acid,28,29 Adt 4-amino-1,2-dithiolane-4-carboxylic acid,30 the axially chiral α-amino acids Bip and Bin31–37 or the Bip system incorporating a crown ether receptor38 have been reported. More recently, the synthesis and properties of antAib, a novel tetrasubstituted α-amino acid of the Ac 5 c type possessing a fused anthracene fluorophore has also been reported 39,40…”

Synthesis and kinetic investigation of the selective acidolysis of para-substituted N-benzyl- or N-phenyl-N-phenylacetyl-α,α-dialkylglycine cyclohexylamides

“…1 Consequently, design of conformational constrained peptides is one of the approaches for development of bioactive species with high activity and selectivity towards a specific receptor. 2,3 Owing to steric crowding within the neighbourhood of the α-carbon atom of α,αdialkyl glycines, conformational rigidity can be obtained by inserting one or more residue of these amino acids into the peptide chain. In addition, special conformational features imparted to the peptide backbone by these amino acid residues 4-7 may be used to modulate activity and selectivity.…”