cis–trans-Amide isomerism of the 3,4-dehydroproline residue, the ‘unpuckered’ proline

Abstract

SummaryProline (Pro) is an outstanding amino acid in various biochemical and physicochemical perspectives, especially when considering the cis–trans isomerism of the peptidyl-Pro amide bond. Elucidation of the roles of Pro in chemical or biological systems and engineering of its features can be addressed with various Pro analogues. Here we report an experimental work investigating the basic physicochemical properties of two Pro analogues which possess a 3,4-double bond: 3,4-dehydroproline and 4-trifluoromethyl-3,4-dehydroproline. Both indicate a flat pyrroline ring in their crystal structures, in agreement with previous theoretical calculations. In solution, the peptide mimics exhibit an almost unchanged equilibrium of the trans/cis ratios compared to that of Pro and 4-trifluoromethylproline derivatives. Finally we demonstrate that the 3,4-double bond in the investigated structures leads to an increase of the amide rotational barriers, presumably due to an interplay with the transition state.

Comparative effects of trifluoromethyl- and methyl-group substitutions in proline

“…These insights have enabled the recent application of 4CF 3 Pro for the labelling and detection of the first transmembrane polyproline helix by means of solid state 19 F NMR. 104 Also, some other ProAs, 4-trifluoromethyl-3,4dehydroproline 105 and difluoro-4,5-methanoprolines 106 can be considered promising fluorine-bearing proline substitutes. However, these compounds exhibit severely compromised stability, in particular, in basic media.…”

Mechanisms and Beyond: Elucidation of Fluxional Dynamics by Exchange NMR Spectroscopy

“…Such rotors may be described as atropdiastereomers involved in dynamic rotation around the Ar−Ar′, R 2 N−CO and Ar−CO bonds, where the rotational barriers are dependent on the location of substituents. Accurate 2D EXSY measurements of dynamics in N ‐acetylated proline and dehydroproline esters 8 (X=H, F) have shown a remarkable increase of their rotation activation energies by the presence of the double bond . An interesting case of flat rotor and stator (Figure ‐III) undergoing a nearly equal exchange is isomeric 2,3‐dimethylanthraquinone‐9‐cyanimides ( 9 ) reported by Günther and separately by Hoz and colleagues .…”

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

“…It can be seen from the experimental data that the basicity reduction from substituents that are parallel and perpendicular to the pyrrolidine ring are different. There are examples showing that the C–F or C–CF 3 fragment in plane with the ammonium dipole reduces the basicity by about Δp K a ≈ 2.2 [ 72 – 73 ]. The same value was obtained for (trifluoromethyl)prolines (Δp K a ≈ 2.3) with equatorially placed C–CF 3 .…”

“…It is interesting to note, that there are only two types of analogues reported to date, where the barriers of the amide-bond rotation are higher compared to proline. These are 3,3-dimethylprolines [ 99 ] and 3,4-dehydroprolines [ 72 ]. It has not been clear however, why these analogues show such an effect, considering that the modifications are quite distant to the rotating amide bond.…”

“…The inability of the analogues to adopt the C 4 -exo conformation in the transition state would explain the energy penalty in the rotation barriers (Figure 9D). In 3,3-dimethylprolines, the isomerization into the C 4 -exo envelope would lead to a steric clash between one of the methyl groups and the backbone carbonyl (k decreases by a factor of 2-6) [99]; in 3,4dehydroprolines, the ring is unable to adopt an envelope conformation due to an endocyclic double bond (k decreases by factor 3) [72].…”