X-ray Diffraction Analysis and Conformational Energy Computations of b-Turn and 310-Helical Peptides Based on a-Amino Acids with an Olefinic Side Chain. Implications for Ring-Closing Metathesis.

The authors describe the x-ray diffraction structure of dipeptide Boc-Aib-L-Mag-NHCH2Ph [Aib = NHC(Me)2CO; Mag = NHC(Me)(CH2CH:CH2)CO] and the results of conformational energy computations on MeCO-L-Mag-NHMe, MeCO-Aib-L-Mag-NHMe and MeCO-L-Mag-Aib-NHMe. On the basis of these data, the authors performed conformational energy computations on the sequence MeCO-Aib-Xaa-(Aib)2-Xaa-Aib-NHMe (I; Xaa = L-Mag) to check the feasibility of ring-closing metathesis (an extensively investigated reaction useful to enhance peptide helicity and metabolic stability) on this 310-helix forming model hexamer with the two olefinic amino acids at the i, i+3 relative positions. Computations were extended to peptides I [Xaa = NHC(Me)(CH2CH2CH:CH2)CO; NHC(Me)(CH2CH2CH2CH:CH2)CO] with extra carbon atoms on the olefinic chain. A comparison was also made with non-methylated peptides I [Xaa = NHCH(CH2CH:CH2)CO, NHCH(CH2CH2CH:CH2)CO, NHCH(CH2CH2CH2CH:CH2)CO]. The authors conclude that, to achieve ring-closing metathesis with an unperturbed 310-helical conformation and a sym. all-hydrocarbon tether, the side-chain length for each of the two i, i+3 olefinic amino acids requires at least five carbon atoms, thereby producing an 18-atom macrocycle.