Probing the Helical Secondary Structure of Short‐Chain β‐Peptides

Abstract

AbstractStructural prerequisites for the stability of the 31 helix of β‐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‐(β‐HVal‐β‐HAla‐β‐HLeu‐Xaa‐β‐HVal‐β‐HAla‐β‐HLeu)‐OMe 13–22 (Xaa = α‐ or β‐amino‐acid residue) and a β‐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 β‐hexapeptide H(‐β‐HVal‐β‐HAla‐β‐HLeu)2‐OH (1) and of the β‐heptapeptide H‐β‐HVal‐β‐HAla‐β‐HLeu‐(S,S)‐β‐HAla(αMe)‐β‐HVal‐β‐HAla‐ β‐HLeu‐OH (22), with a central (2S,3S)‐3‐amino‐2‐methylbutanoic‐acid residue, confirm the helical structure of such β‐peptides (previously discovered in pyridine solution) (Fig.3 and Tables 1–5). The CD spectra of helical β‐peptides, the residues of which were prepared by (retentive) Arndt‐Eistert homologation of the (S)‐ or L‐α‐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)‐β‐HAla, β‐HAib, (R,S)‐β‐HAla(α Me), or N‐Me‐β‐HAla) in the central position of the β‐heptapeptide derivatives A (see 17, 18, 20, or 21, resp.) causes the CD minimum to disappear. Also, the β‐heptadepsipetide 25 (missing H‐bond) and the β‐heptapeptide analogs with a single α‐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).