The Side-chain Hydroxy Groups of a Cyclic α,α-Disubstituted α-Amino Acid Promote Oligopeptide 310-Helix Packing in the Crystalline State

A single chiral cyclic alpha, alpha-disubstituted amino acid with side-chain methoxymethyl (MOM) protecting groups, (3S, 4S) 21-amino-(3,4-dimethoxymethoxy) cyclopentanecarboxylic acid [(S, S)-Ac(5)c(dOMOM)], or side-chain hydroxy groups, (3S, 4S) 21-amino-(3,4-dihydroxy) cyclopentanecarboxylic acid [(S, S)-Ac(5)c(dOH)], was attached to the N-terminal or C-terminal position of alpha-aminoisobutyric acid (Aib) tetrapeptide segments; i.e., we designed and synthesized four pentapeptides, Cbz-[(S, S)-Ac(5)c(dOMOM)]-(Aib) (4)-OEt (1), Cbz-[(S, S)-Ac(5)c(dOH)]( Aib) (4)-OEt (2), Cbz-(Aib) (4)-[(S, S)-Ac(5)c(dOMOM)]-OMe (3), and Cbz-(Aib) (4)-[(S, S)-Ac(5)c(dOH)]-OMe (4). We then analyzed the peptides' structures in the crystalline state. The four peptides all folded into 3(10)-helical structures; 1 formed a left-handed (M) 3(10)-helix, 2 formed a mixture of right-handed (P) and (M) 3(10)-helices, 3 formed a mixture of (P) and (M) 3(10)-helices, and 4 formed a (P) 3(10)-helix, respectively. In packing mode, the molecules of peptides 1 and 3, which both possessed an Ac(5)c(dOMOM) residue, were connected by intermolecular hydrogen bonds along the peptide backbone (N-H center dot center dot center dot O type). On the other hand, the packing of peptides 2 and 4, which both contained an Ac(5)c(dOH) residue, was based on intermolecular hydrogen bonds derived from both the peptide backbone and the side-chain hydroxy groups of the amino acid Ac(5)c(dOH) (O-H center dot center dot center dot O type). (C) 2016 Wiley Periodicals, Inc.