Cis-Trans Conformational Analysis of δ-Azaproline in Peptides

The cis-trans isomerization and conformer specificity of delta-azaproline and its carbamate-protected form in linear and cyclic peptides were investigated using NMR and alpha-chymotrypsin assay. Comparisons of the chemical shift value of the alpha-hydrogen in each case of delta-azaproline-containing peptides with conformer-specific locked diketopiperazines reveal the fact that an upfield chemical shift value corresponds to cis conformer and a downfield value corresponds to a trans conformer. delta-Azaproline adopts cis-conformation in simple amides, dipeptides, and tripeptides whereas its carbamate-protected form adopts trans-conformation. In the case of longer, linear or cyclic peptides, vice versa results are obtained. Interestingly, in all these peptides exclusively one conformer, either cis or trans, is stabilized. This cis-trans isomerization is independent of both temperature and solvents; only the delta-nitrogen protecting group plays key role in the isomerization. delta-Azaproline is conformer-specific in either of its protected or deprotected forms, which is a unique property of this proline. Unlike other covalently modified proline surrogates, this isomerization of delta-azaproline can be tuned easily by a protecting group. The mechanism of cis-trans isomerization of delta-azaproline during deprotection and reprotection is supported by theoretical calculations.