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

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 )‐ 2.6 1 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 )‐ 3 1 helix of 5‐Å pitch, 14‐membered H‐bonded rings) and with the familiar right ‐handed, so‐called α‐helix of α‐peptides (( P )‐ 3.6 1 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.