Design, synthesis, NMR-solution and X-ray crystal structure of N-acyl-gamma-dipeptide amides that form a beta II '-type turn

Conformational analysis of gamma -amino acids with substituents in the 2-po sition reveals that an N-acyl-gamma -dipeptide amide built of two enantiome ric residues of unlike configuration will form a 14-membered H-bonded ring, i.e., a gamma -peptidic turn (Figs. 1 - 3). The diastereoselective prepara tion of the required building blocks was achieved by alkylation of the doub ly lithiated N-Boc-protected 4-aminoalkanoates, which, in turn, are readily available from the corresponding (R)- or (S)-alpha -amino acids (Scheme I) . Coupling two such gamma -amino acid derivatives gave N-acetyl and N-[(ter t-butoxy)carbonyl] (Boc) dipeptide methyl amides (1 and 10, resp.; Fig. 2, Scheme 2); both formed crystals suitable for X-ray analysis, which confirme d 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 f act that more stable secondary structures are formed with a decreasing numb er of residues, and with increasing degree of predictability, as we go from alpha- to beta- to gamma -peptides. Implications of the superimposable geo metries of the actual turn segments (with amide bonds flanked by two quasi- equatorial substituents) in alpha-, beta, and. gamma -peptidic turns are di scussed.