gamma-peptides forming more stable secondary structures than alpha-peptides: Synthesis and helical NMR-solution structure of the gamma-hexapeptide analog of H-(Val-Ala-Leu)(2)-OH

摘要

For a comparison with the corresponding alpha- and beta-hexapeptides H-(Val-Ala-Leu)(2)-OH (A) and H-(beta-HVal-beta-HAla-beta-HLeu)(2)-OH (B), we have now prepared the corresponding gamma-hexapeptide 1 built from the homochirally similar (S)-4-aminobutanoic acid, (R)-4-amino-5-methylhexanoic acid, and (R)-4-amino-6-methylheptancic acid. The precursors were prepared either by double Arndt-Eistert homologation of the protected amino acids Boc-Val-OH, Boc-Ala-OH, and Poe-Leu-OH (Schemes 1 and 2), or by the superior route involving olefination/hydrogenation of the corresponding aldehydes (Boc-valinal, Boc-alaninal, and Boc-leucinal; Scheme 3). Conventional peptide-coupling methodology (EDC/HOBt) furnished the gamma-hexapeptide 1 (through the intermediate gamma-di- and gamma-tripeptide derivatives 9-11). Analysis of NMR measurements in (D-5)pyridine and CD3OH solution (COSY, TOCSY, HSQC, HMBC, ROESY) reveals that the gamma-hexapeptide 1 adopts a right-handed helical structure ((P)-2.6(1) helix of ca. 5-Angstrom pitch, containing 14-membered H-bonded rings) which is to be compared with the left-handed helix of the corresponding beta-peptide B ((M)-3(1) helix of 5-Angstrom pitch, 14-membered H-bonded rings) and with the familiar right-handed, so-called alpha-helix of alpha-peptides ((P)3.6(1) helix of 5.4-Angstrom, pitch, 13-membered rings). Like the helix sense, the helix dipole reverses when going from alpha- (N +--> C) to beta- (C +--> N) to gamma-peptides (N +--> C). The surprising difference between the natural alpha-, and the analogous beta- and gamma-peptides is that the helix stability increases upon homologation of the residues. [References: 45]