Design, Synthesis, and Conformational Analysis of Proposed β‐Turn Mimics from Isoxazoline‐Cyclopentane Aminols

Abstract

Constrained aminols from oxazanorbornene derivatives have the geometrical features to be used as β-turn inducers. Four different stereoisomers were prepared and spectroscopically characterized (MD calculations, NMR-titration and VT-NMR experiments). Temperature coefficients in DMSO are indicative for the existence of an intramolecular hydrogen bond. Chirooptical properties revealed a β-turn arrangement of all the synthesized compounds, where, depending on the absolute configuration of the cyclopentane spacer, they can be labeled as left- or right-handed turns.

Cyclopenta[d]isoxazoline β-Turn Mimics: Synthetic Approach, Turn Driving Force, Scope, and Limitations

“…All of the compounds reported above were separated and found identical to authentic specimens previously synthesized. 13…”

“…Noteworthy, these values are remarkably close to those observed for the model malonic derivatives. 13 Regarding the l -valine derivatives, the CD profile of compound 14a , a left β-turn, has a positive absorption band at 213.5 nm and a second negative band centered at 227.1 nm. 19 On the other side, the CD spectrum of 15a shows a comparable and specular trend with a negative absorption band at 211.3 nm and a second positive band centered at 225.9 nm, consistent for a right β-turn.…”

“…These values are again strictly close to those observed for the glycine derivatives and the model malonic ones. 13…”

“…Recently, we have presented our approach toward the preliminary design of original nonpeptidic turn inducers 13 based on a new class of cyclopenta[ d ]isoxazoline aminols using the nitrosocarbonyl (RCONO, 3 ) chemistry (Scheme 1). 14…”

“…In our “proof-of-concept” work, 13 we promised to develop further experiments to verify the influence of the two side chain features on the type of turn, gaining a better understanding of the applicability/reliability/robustness of these scaffolds as β-turn inducers. We wish to present here the elongation studies from the hydroxy and amino groups with side chains incorporating amino acidic residues (alanine, glycine, and valine) and the characterizations of the corresponding diastereoisomeric turn structures through NMR and circular dichroism (CD) techniques.…”