Effect of progressive benzyl substitution on the conformations of aminocaproic acid-cyclized dipeptides

Abstract

The constraint of dipeptides into a beta-turn conformation can be accomplished by linking the two ends of a standard dipeptide with a linker derived from aminocaproic acid (Aca). To elucidate the possibility of using substituted Aca linkers in peptidomimetic design, a series of five macrocycles composed of a monobenzylated Aca linker (containing the benzyl group on each of the five methylene groups of the parent linker) and Gly-Gly were synthesized. The requisite linkers were made by regiochemically controlled ring expansion techniques (for substitution on Aca positions C-3, C-4, or C-5), an Evans alkylation route (for C-2), or by chain extension of L-phenylalanal (for C-6). The solution-phase conformations of the macrocycles were examined by NMR and CD techniques; in addition, crystal structures of the C-4- and C-6-benzyl-substituted linkers were obtained. Four out of the five macrocycles were found to exist with the dipeptide portion taking up either a type II or II' beta-turn conformation, but the Gly-Gly unit in the compound derived from 4-benzyl-Aca did not correspond to one of the standard beta-turn types.