Duttagupta Indranil, Misra Debojyoti, Bhunya Sourav, Paul Ankan, Sinha Surajit
Department of Organic Chemistry and ‡Raman Centre for Atomic, Optical and Molecular Physics, Indian Association for the Cultivation of Science , Jadavpur, Kolkata 700 032, India.
J Org Chem. 2015 Nov 6;80(21):10585-604. doi: 10.1021/acs.joc.5b01668. Epub 2015 Oct 20.
The cis-trans isomerization and conformer specificity of δ-azaproline and its carbamate-protected form in linear and cyclic peptides were investigated using NMR and α-chymotrypsin assay. Comparisons of the chemical shift value of the α-hydrogen in each case of δ-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. δ-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 δ-nitrogen protecting group plays key role in the isomerization. δ-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 δ-azaproline can be tuned easily by a protecting group. The mechanism of cis-trans isomerization of δ-azaproline during deprotection and reprotection is supported by theoretical calculations.
