Linear and Cyclic Hybrids of Alternating Thiophene-Amino Acid Units: Synthesis and Effects of Chirality on Conformation and Molecular Packing

The dipeptide isostere 5‐aminothiophene carboxylic acid has been combined with L‐phenylalanine moieties to provide linear and cyclic hybrid oligopeptides. A suitable protecting group strategy and appropriate coupling methods have been developed to guarantee a high degree of enantiopurity of the resulting amides. Cyclic tetraamides have been efficiently obtained by macrocyclization of the linear derivatives. In the case of racemized cyclization precursors, two diastereomeric macrocycles (S,S/R,R and meso) have been isolated. Their crystal structures show clear effects of the stereogenic centers on the ring conformations and molecular packing. Chirality matters! Different synthetic routes toward linear and cyclic hybrid oligoamides with backbones containing alternating thiophene and phenylalanine units have been explored. Methods to retain the enantiopurity of the α‐amino acid units have been developed. Depending on the stereogenic centers of the cyclic tetraamide derivatives, different crystal structures with crown or boat conformations of the rings and different molecular packings have been observed (see scheme; Cbz=carbenzyloxy; Bn=benzyl).