DESTABILIZATION OF THE 3(10)-HELIX IN PEPTIDES BASED ON C-ALPHA-TETRASUBSTITUTED ALPHA-AMINO-ACIDS BY MAIN-CHAIN TO SIDE-CHAIN HYDROGEN-BONDS

The homooligopeptide series based on O,O-isopropylidene-alpha-hydroxym ethylserine from dimer through pentamer has been synthesized to examin e the conformational preferences of this new C-alpha-tetrasubstituted cr-amino acid characterized by concomitant C-i(alpha <---->) C-i(alpha ) cyclization and presence of two ether oxygen atoms in the gamma-posi tions of the six-membered ring 1,3-dioxane system. To this aim we have exploited X-ray diffraction in the crystal state and FTIR absorption and H-1 NMR techniques in solution; The results obtained are compared with those of the homooligopeptides based on the related cyclohexane-c ontaining C-alpha-tetrasubstituted residue. We conclude that in the fo rmer peptides a competition takes place between the classical intramol ecular (peptide) C=O...H-N (peptide) H-bonds, stabilizing the beta-ben d/3(10)-helical structures, and the newly discovered (peptide) Ni+1l-H ...O(i)gamma (side-chain ether) intramolecular H-bonds. The extent of regular (incipient) 3(10)-helix formation, where this latter type of I I-bond is absent, tends to increase as peptide main-chain length incre ases. As a result of this intramolecular N-H...O-gamma interaction, th e critical main-chain length for 3(10)-helix formation in the crystal state shifts from the shortest possible oligomer, the terminally prote cted trimer, in the cyclohexane series to the pentamer in the 1,3-diox ane series. Interestingly, a Strict correlation has been found between the observed (peptide) Ni+1-H...O-i(gamma) (side-chain ether) intramo lecular H-bond and (i) the backbone psi torsion angle of the i residue (extended), and (ii) the disposition of the a-amino substituent in th e 1,3-dioxane ring of the i + 1 residue (axial).