X-Pro peptides: solution and solid-state conformation of benzyloxycarbonyl-(Aib-Pro)methyl ester, a type I β-turn

Abstract

The synthesis of the tetrapeptide benzyloxycarbonyl(α-aminoisobutyryl-L-prolyl)₂-methyl ester (Z-(Aib-Pro)₂-OMe) and an analysis of its conformation in solution and the solid state are reported. Stepwise synthesis using dicyclohexylcarbodiimide leads to racemization at Pro(2). Evidence for the presence of diastereomeric tetrapeptides is obtained from 270-MHz¹H-nmr and 67.89-MHz ¹³C-nmr. The all-L tetrapeptide is obtained by fractional crystallization from ethyl acetate. The NH of Aib(3) is shown to be involved in an intramo-lecular hydrogen bond by variable-temperature ¹H-nmr and the solvent dependence of NH chemical shifts. The results are consistent with a -turn conformation with Aib(1) and Pro(2) at the corners stabilized by a 4 →1 hydrogen bond. The molecule crystallizes in the space group P2₁2₁2₁, with a = 8.839, b = 14.938, and c = 22.015 Å. The structure has been refined to an R value of 0.051. The peptide backbone is all-trans, and a 4 →1 hydrogen bond, between the CO group of the urethane moiety and Aib(3) NH, is observed. Aib(1) and Pro(2) occupy the corner positions of a type I β-turn with Φ= -55.4°, = Ψ=-31.3° for Aib(1) and Φ= -71.6°, Ψ= -38° for Pro(2). The tertiary amide unit linking Pro(2) and Aib(3) is significantly distorted from planarity ( Δω= 14.3°).