Design, Synthesis, NMR-Solution and X-Ray Crystal Structure ofN-Acyl-γ-dipeptide Amides That Form aβII′-Type Turn

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Conformational analysis of γ-amino acids with substituents in the 2-position reveals that an N-acyl-γ-dipeptide amide built of two enantiomeric residues of unlike configuration will form a 14-membered H-bonded ring, i.e., a γ-peptidic turn (Figs. 1 – 3). The diastereoselective preparation of the required building blocks was achieved by alkylation of the doubly lithiated N-Boc-protected 4-aminoalkanoates, which, in turn, are readily available from the corresponding (R)- or (S)-α-amino acids (Scheme 1). Coupling two such γ-amino acid derivatives gave N-acetyl and N-[(tert-butoxy)carbonyl] (Boc) dipeptide methyl amides (1 and 10, resp.; Fig. 2, Scheme 2); both formed crystals suitable for X-ray analysis, which confirmed the turn structures in the solid state (Fig. 4 and Table 4). NMR Analysis of the acetyl derivative 1 in CD3OH, with full chemical-shift and coupling assignments, and, including a 300-ms ROESY measurement, revealed that the predicted turn structure is also present in solution (Fig. 5 and Tables 1 – 3). The results described here are yet another piece of evidence for the fact that more stable secondary structures are formed with a decreasing number of residues, and with increasing degree of predictability, as we go from α- to β- to γ-peptides. Implications of the superimposable geometries of the actual turn segments (with amide bonds flanked by two quasi-equatorial substituents) in α-, β-, and γ-peptidic turns are discussed.