γ-Turn Mimicry with Benzodiazepinones and Pyrrolobenzodiazepinones Synthesized from a Common Amino Ketone Intermediate

Abstract

To investigate diazepinone analogues as γ-turn mimics, seven 1,4-benzodiazepin-2-ones 6 and fourteen pyrrolo[1,2-d][1,4]benzodiazepin-6-ones 4 and 5 were synthesized from 1-(2-aminophenyl)pent-4-en-1-one (7). Acylation of aniline 7 with N-Boc-amino acids, olefin oxidation, Boc removal, and intramolecular Paal-Knorr condensation gave 4 and 5. Alternatively, Boc removal prior to oxidation gave benzodiazepinones 6, which were converted to 4 by ozonolysis and cyclization. Comparison of dihedral angle values for the amino acid component from X-ray analyses of 4g, 5f, and 6f and related diazepinones has catalogued the manner by which ring substituents affect the component's ability to mimic the central residues of γ-turns.

Fishing in the Toolbox of Cyclic Turn Mimics: a Literature Overview of the Last Decade

“…In this respect, in 2015 Dorr et al [70] investigated about diazepin-2-ones conformational behavior producing a library of compounds of general formula 120-122 synthesized from a common ketone intermediate 119 (Scheme 26).…”

An Update on the Synthesis of Pyrrolo[1,4]benzodiazepines

“…They also have the ability to mimic natural γ- and β-turn peptide secondary structure. In order to investigate novel diazepinone analogues as potential γ-turn mimics, Dörr and Lubell [100] synthesized PBDs 312a – g and 314a – g (Scheme 58) and examined them by X-ray diffraction since X-ray structural analysis of certain diazepin-2-ones has revealed that their amino acid components adopt dihedral angle values similar to those of the central residue in a γ-turn. The starting point for the synthesis of these PBDs is 1-(2-aminophenyl)pent-4-en-1-one ( 307 ) which was coupled to Boc- l -α-amino acids 308a – g using N , N ′-dicyclohexylcarbodiimide (DCC), and 4-dimethyl-aminopyridine (DMAP) while the addition of N -hydroxybenzotriazole (HOBt) prevented racemisation so that amides 309a – g were obtained, after chromatography, in 67%–97% yields and >93% enantiomeric excess.…”

Protein/peptide secondary structural mimics: design, characterization, and modulation of protein–protein interactions

“…However, the crystal structure exhibited a different folding model for this group of oligomer. An increasing number of novel turn mimics are being developed with a more specic purpose of targeting, such as benzazepin-3-one or benzodiazepinone derivatives as a new group of b-turn 74 or g-turn mimics, 75 respectively. More complicated motifs with turn structures as a b-hairpin motif have also been mimicked 76 and characterized.…”