STEREOCHEMICAL STUDIES ON CYCLIC-PEPTIDES .9. CONFORMATIONAL STUDIES ON CYCLIC TETRAPEPTIDES CONTAINING ALTERNATING CIS-PEPTIDE AND TRANS-PEPTIDE UNITS

Conformational analyses of cyclic tetrapeptides consisting of alternating cis and trans peptide units were made using contact criteria and energy calculations. The study was restricted to those structures having a symmetry element in the backbone ring, such as a 2-fold axis (d) or a center of inversion (i). There are 2 distinct types of conformations, which are stereochemically favorable corresponding to each of 2-fold and inversion-symmetrical structures, designated as d1, d2 (for 2-fold symmetrical) and i1,i2 (for inversion-symmetrical). Among these, the i1 type has the lowest energy when glycly residues occur at all 4 .alpha.-C atoms. With the glycyl residue at all 4 .alpha.-C atoms, methyl substitution at the cis peptide N atoms is possible in all the 4 types, whereas the substitution at trans peptide N atoms is possible only for the i1 type. Thus only in the i1 type can all the N atoms be methylated simulatneously. The conformation of the molecule in the crystal structure of cyclotetrasarcosyl belongs to the i1 type. When alanyl residues occur at all 4 .alpha.-C atoms, the possible symmetrical type is dependent on the enantiomorphic form and the actual sequence of the alanyl residues. The methyl substitution at peptide N atoms for cyclic tetrapeptides having alanyl residues causes more stereochemical restriction in the allowed conformations than with glycyl residues. The prolyl residue can be incorporated favorably at the cis-trans junction of both d and i types of structures. The results of the present study are compared with the data on cyclic tetrapeptides available for the crystal structure and NMR studies. The results show an overall agreement both regarding the type of symmetry and the conformational parameters.