γ‐Peptides Forming More Stable Secondary Structures than α‐Peptides: Synthesis and helical NMR‐solution structure of the γ‐hexapeptide analog of H‐(Val‐Ala‐Leu)2‐OH

Abstract

For a comparison with the corresponding α‐ and β‐hexapeptides H‐(Val‐Ala‐Leu)2‐OH (A) and H‐(β‐HVal‐β‐HAla‐β‐HLeu)2‐OH (B), we have now prepared the corresponding γ‐hexapeptide 1 built from the homochirally similar (S)‐4‐aminobutanoic acid, (R)‐4‐amino‐5‐methylhexanoic acid, and (R)‐4‐amino‐6‐methylheptanoic acid. The precursors were prepared either by double Arndt‐Eistert homologation of the protected amino acids Boc‐Val‐OH, Boc‐Ala‐OH, and Boc‐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 γ‐hexapeptide 1 (through the intermediate γ‐di‐ and γ‐tripeptide derivatives 9–11). Analysis of NMR measurements in (D 5)pyridine and CD 3 OH solution (COSY, TOCSY, HSQC, HMBC, ROESY) reveals that the γ‐hexapeptide 1 adopts a right‐handed helical structure ((P)‐2.61 helix of ca. 5‐Å pitch, containing 14‐membered H‐bonded rings) which is to be compared with the left‐handed helix of the corresponding β‐peptide B ((M)‐31 helix of 5‐Å pitch, 14‐membered H‐bonded rings) and with the familiar right‐handed, so‐called α‐helix of α‐peptides ((P)‐3.61 helix of 5.4‐Å pitch, 13‐membered rings). Like the helix sense, the helix dipole reverses when going from α‐, (N + → C) to β‐(C + → N) to γ‐peptides (N + → C). The surprising difference between the natural α‐, and the analogous β‐ and γ‐peptides is that the helix stability increases upon homologation of the residues.