Trifluoromethylated Proline Surrogates as Part of “Pro–Pro” Turn‐Inducing Templates

Proline is often found as a turn inducer in peptide or protein domains. Exploitation of its restricted conformational freedom led to the development of the d‐Pro‐l‐Pro (corresponding to (R)‐Pro–(S)‐Pro) segment as a “templating” unit, frequently used in the design of β‐hairpin peptidomimetics, in which conformational stability is, however, inherently linked to the cis–trans isomerization of the prolyl amide bonds. In this context, the stereoelectronic properties of the CF3 group can aid in conformational control. Herein, the impact of α‐trifluoromethylated proline analogues is examined for the design of enhanced β‐turn inducers. A theoretical conformational study permitted the dipeptide (R)‐Pro–(R)‐TfmOxa (TfmOxa: 2‐trifluoromethyloxazolidine‐2‐carboxylic acid) to be selected as a template with an increased trans–cis rotational energy barrier. NMR spectroscopic analysis of the Ac‐(R)‐Pro–(R)‐TfmOxa–(S)‐Val‐OtBu β‐turn model, obtained through an original synthetic pathway, validated the prevalence of a major trans–trans conformer and indicated the presence of an internal hydrogen bond. Altogether, it was shown that the (R)‐Pro–(R)‐TfmOxa template fulfilled all crucial β‐turn‐inducer criteria. Stabilizing twists and turns: The amino acid 2‐trifluoromethyloxazolidine‐2‐carboxylic acid (TfmOxa) induces an enhanced conformational stability in diproline turn‐inducing templates. An in silico and NMR spectroscopy based conformational study has demonstrated a strong prevalence for a trans–trans geometry and typical i,i+3 hydrogen bond requirement in peptidic β‐turn structures.