Synthesis and CD Spectra of Fluoro‐ and Hydroxy‐Substituted β‐Peptides

Abstract β‐Amino acids 1–3 with OH and F substituents in the α‐position have been prepared (Scheme) from the natural (S)‐α‐amino acids alanine, valine, and leucine, and incorporated into β‐hexa‐ and β‐heptapeptides 4–12. The peptide syntheses were performed according to a conventional solution strategy (Boc/Bn protection) with fragment coupling. The new β‐peptides with (series a) and without (series b) terminal protection were isolated in HPLC‐pure form and characterized by NMR spectroscopy and MALDI mass spectrometry. The chemical properties as well as the patterns of the CD spectra (Figs. 3–5) depend upon constitution (OH, F, F2 substitution) and configuration (l or u) of the amino acid residues, upon the total number of OH and F substituents in the peptide chain, and upon the solvent used (H2O, MeOH, CF3CH2OH, (CF3)2CHOH). No reliable clues regarding the structures can be obtained from these CD spectra. Only a full NMR analysis will be able to answer the questions: a) with which known secondary structures (Figs. 1 and 2) of β‐peptides are the OH and F derivatives compatible? b) Are new secondary structures enforced by the polar and/or H‐bonding backbone substituents? Furthermore, the β‐peptides described here will enable us to study changes in chemical, enzymatic, and metabolic stability, and in physiological properties caused by the heteroatoms.