Conformational mimicry. 1. 1,5-disubstituted tetrazole ring as a surrogate for the cis amide bond

Assessment of the conformational implications of chemical modification is an important aspect of analogue design. A new procedure, the assessment of conformational mimicry, which determines the percentage of sterically accessible conformations for the parent compound also available to the analogue, is used to show that 88% of the conformers allowed for the cis amide bond are also available to peptides in which the amide bond is replaced by a 1,5-disubstituted tetrazole ring that locks the amide bond in the cis conformer. This analysis was made possible by the crystal structure of a cyclic dipeptide, cyclo[L-Phe-ψ(CN₄)-L-Ala], determined in this paper. The crystals of the diketopiperazine analogue are monoclinic, space group P2₁/c, with cell parameters a = 11.677 (1), b = 7.742 (1), c = 13.086 (1) Å; β=93.39 (1)°; Z = 4; and D_calcd= 1.368 g cm^-3. The tetrazole ring system is planar with all five torsional angles equal to 0°. The diketopiperazine ring system is nearly planar, and the phenylalanine ring adopts the flagpole orientation over the cyclic dipeptide. A procedure for the preparation of this class of peptide analogues by synthetic routes avoiding racemization of the amino acids of the starting dipeptide is demonstrated. The tetrazole ring provides, therefore, a synthetic probe for the role of cis-trans isomerism of N-alkylamide bonds, such as that of proline, in molecular recognition.