Probing the helical secondary structure of short-chain beta-peptides

Structural prerequisites for the stability of the 3(1) helix of beta-peptides can be defined from inspection of models (Figs.1 and 2): lateral non-H-substituents in 2- and 3-position on the 3-amino-acid residues of the helix are allowed, axial ones are forbidden. To be able to test this prediction, we synthesized a series of heptapeptide derivatives Boc-(beta-HVal-beta-HA1a-beta-HLeu-Xaa-beta-HVal-beta-HAla-B-HLeu)-OMe 13-22 (Xaa = alpha- or beta-amino-acid residue) and a beta-depsipeptide 25 with a central (S)-3-hydroxybutanoic-acid residue (Xaa = -OCH(Me)CH2C(O)-) (Schemes 1-3). Detailed NMR analysis (DQF-COSY, HSQC: HMBC, ROESY, and TOCSY experiments) in methanol solution of the beta-hexapeptide H(-beta-HVal-beta-HAla-beta-HLeu)(2)-OH (1) and of the beta-heptapeptide H-beta-HVal-beta-HAla-beta-HLeu-(S,S)-beta-HAla(alpha Me)-beta-HVal-beta-HAla-beta-HLeu-OH (22), with a central (2S,3S)-3-amino-2-methylbutanoic-acid residue, confirm the helical structure of such beta-peptides (previously discovered in pyridine solution) (Fig. 3 and Tables 1-5). The CD spectra of helical beta-peptides, the residues of which were prepared by (retentive) Arndt-Eistert homologation of the (S)- or L-alpha-amino acids, show a trough at 215 nm. Thus, this characteristic pattern of the CD spectra was taken as an indicator for the presence of a helix in methanol solutions of compounds 13-22 and 25 (including partially and fully deprotected forms) (Figs. 4-6). The results fully confirm predicted structural effects: incorporation of a single 'wrong' residue ((R)-beta-HAla, beta-HAib, (R,S)-beta-HAla(alpha Me), or N-Me-beta-HAla) in the central position of the beta-heptapeptide derivatives A (see 17, 18, 20, or 21, resp.) causes the CD minimum to disappear. Also, the beta-heptadepsipetide 25 (missing H-bond) and the beta-heptapeptide analogs with a single alpha-amino-acid moiety in the middle (13 and 14) are not helical, according to this analysis. An interesting case is the heptapeptide 15 with the central achiral, unsubstituted 3-aminopropanoic-acid moiety: helical conformation appears to depend upon the presence or absence of terminal protection and upon the solvent (MeOH vs. MeOH/H2O).