Amino equatorial effect of a six-membered ring amino acid on its peptide 310- and α-helices

Two diastereomeric six-membered ring α,α-disubstituted α-amino acids (1R,3R)- and (1S,3R)-1-amino-3-methylcyclohexanecarboxylic acids (Ac6c3M); side-chain restricted leucine analogs, were stereoselectively synthesized from (3R)-3-methylcyclohexanone by a Bucherer–Bergs or Strecker reaction. Two series of homo-chiral homopeptides Cbz-[(1R,3R)- and (1S,3R)-Ac6c3M]n-OMe, up to hexapeptides (n=6), were prepared, respectively, and the preferred conformations of cyclohexane rings of amino acid residues and the peptide-backbones were studied. In solution, these peptides formed helical structures, but the helical-screw control to one-handedness was not possible for the hexapeptide length. In the crystal state, all (1R,3R)-Ac6c3M residues formed cyclohexane chair form conformations with a 3-methyl substituent at equatorial orientation and an amino group at the axial position, whereas all (1S,3R)-Ac6c3M residues assumed cyclohexane chair forms with the 3-methyl and amino groups at equatorial orientations. The preferred peptide-backbone structure of (1R,3R)-Ac6c3M hexapeptide had (P) and (M) 310-helices, and that of (1S,3R)-Ac6c3M hexapeptide had (P) and (M) α-helices in the crystal state.

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