Stabilization of Azapeptides by N(amide)....HN(amide) Hydrogen Bonds.

Stabilization of Azapeptides by N(amide)....HN(amide) Hydrogen Bonds.

An unusual Namide∙∙∙H–Namide hydrogen bond (HB) was previously proposed to stabilize the azapeptide β-turns. Herein, we provide experimental evidence for Namide···H–Namide HB and show that this HB endows a stabilization of 1-3 kcal.mol-1 and enforces the trans-cis-trans (t-c-t) and cis-cis-trans (c-c-t) amide bond conformations in azapeptides and N-methyl-azapeptides, respectively. Our results indicate that these Namide···H–Namide HBs can have stabilizing contributions even in short azapeptides that cannot fold to form β-turns.

This work was recently ublished in Organic Letters (Org. Lett.  2021, https://doi.org/10.1021/acs.orglett.1c01111)