Structural biology relies heavily on NMR studies of peptides and proteins that are uniformly or selectively labeled with NMR-active isotopes (2H, 13C, 15N, 19F). One of the most informative approaches to analyze membrane-active peptides in their natural membrane-bound form is solid-state 19F NMR spectroscopy in oriented lipid bilayers.[1] The main advantages of this approach are the exquisite sensitivity of fluorine, the lack of any natural abundance background, the simplicity of the NMR experiment and data analysis, especially when CF3-substituted amino acids are used as labels (CF3 labels). Numerous applications have demonstrated utility of the designated CF3 labels 1–4,[2] incorporated into peptides in the place of a bulky hydrophobic amino acid (1, 2), αaminoisobutyric acid (3), or proline (4).[3] The 19F NMR parameters from several selectively labeled analogues serve as orientational constraints to yield the backbone conformation, alignment, and dynamic behavior of the peptide in the lipid bilayer. The structure calculation relies entirely on the fact that the CF3 group must be attached to the peptide backbone with a fixed and well-defined angle, as seen in 1–4.

All the available CF3 labels 1–4 share the common characteristic of having hydrophobic side chains. Therefore, they can only be used as NMR reporters in the place of similarly hydrophobic residues.[2, 3] The substitution of any polar amino acid with one of the CF3 labels 1–4 might disturb the conformation and function of a peptide; this is highly undesirable in structural studies.[1b, d, 2d, e] The obvious lack of appropriate polar and/or charged CF3 labels prompted us to develop a novel molecular framework for CF3-substituted amino acids with functionalized side chains. Here, we report on the design and synthesis of a CF3-substituted serine/threonine analogue, as well as on the validation of its use in peptide structural studies. To our knowledge, this is the first 19F label for solid-state NMR analysis that possesses a polar side chain.