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

Abstract

Abstract Structural prerequisites for the stability of the 3 1 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)CH 2 C(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 (2 S ,3 S )‐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/H 2 O).