Effect of Differential Backbone Di‐substitution of Gamma Amino Acid Residues on the Conformation and Assembly of their Fmoc Derivatives in Solid and Solution States

Abstract

We studied the effect of variable backbone dimethyl-substitution of γ amino acid residues (γ2,2 , γ3,3 and γ4,4 ) on the conformation and assembly, in crystals and solution of their Fmoc derivatives. The crystal structure of γ2,2 and γ4,4 derivatives showed distinct conformations (open/close for γ2,2 /γ4,4 ) that differed in torsion angles, hydrogen-bonding and most importantly the π-π Fmoc-stacking interactions (relatively favourable for γ4,4 -close). Fmoc derivatives existed in an equilibrium between major-monomeric (low energy, non-hydrogen bonded) and minor-dimeric (high energy, hydrogen bonded) populations in solution. The rate of major/minor population exchange was dependent on the position of substitution, highest being for γ4,4 derivative. In solution, assembly of Fmoc derivatives was solvent dependent, but it was independent of the position of geminal substitution. Crystallization was primarily governed by the stabilization of high-energy dimer by favourable π-π stacking involving Fmoc moieties. High free-energy of the dimers (γ2,2 -close, γ3,3 -open/close) offset favourable stacking interactions and hindered crystallization.