A macrocycle containing two biphenyl and two alanine subunits, synthesis and conformation in solution

Abstract

The synthesis and solution conformation of the macrocycle cyclo(- 2 -Ala) 2 3 is presented. The compound 3 contains two alanine and two molecules of the novel pseudoamino acid 2-aminomethyl-2'-carboxymethylbiphenyl 2 , in the ring. A phthalimido-protected derivative of 2 is obtained in three steps from diphenic anhydride. The compound 2 is coupled to H-AlaOCH 3 and the resulting ‘dipeptide’ dimerizes at the conditions of an azide coupling to 3 (20%). The macrocycle 3 exists in three diastereomeric forms 3A , 3B and 3C . which can be separated by HPLC. The form with R,S configuration of the biphenyl groups has C 1 symmetry ( 3C ). The one- and two-dimensional 1H-NMR data of 3C support a structure where the biphenyl groups are orientated in an orthogonal arrangement. One alanine is in an equatorial C 7 conformation, the other alanine is part of a stretched peptide chain. The forms 3A and 3B with C 2, symmetry exist probably as equilibrating structures in solution. The NMR data can be explained with β-sheet conformations as well as with more bent structures containing γ -loops.