Resolution of (1R,2R)- and (1S,2S)-cyclic constrained phenylalanine analogues (c6Phe). Conformations of (1R,2R)- and (1S,2S)-c6Phe containing peptides

Article abstract of DOI:10.1016/S0040-4020(98)00692-9

The enantiomerically pure (1R,2R)- and (1S,2S)-1-amino-2- phenylcyclohexane-1-carboxylic acids (c₆Phe) 3a and 3b were synthesized in good yields by a resolution method described by Obrecht. This method involves the formation of the diastereoisomeric peptides 7a and 7b followed by chromatographic separation. The free (1R,2R)- and (1S,2S)-c₆Phe amino acids (3a and 3b) were converted into appropriately protected phenylalanine analogues 10a and 10b for possible use in peptide synthesis. The conformational analysis in solution, of these peptides revealed thin dipeptide 3a shows an extended-type conformation, while dipeptide 3b shows a type I β-turn geometry. In addition, we have prepared the unsaturated peptides 11a and 11b and the structure of 11b, determined by X-ray analysis, also shows a type I β-turn conformation in the solid state. The NMR data of this dipeptide (11b) allowed the characterisation of the type I β-turn conformation in solution and established to be similar to the solid state structure. These results suggest that c₆Phe can be used as building blocks to stabilise type I β-turns or extended chains in peptides, depending on their absolute configurations.