Lactam Amide Spinning

Abstract

The amide rotation of cis-trans lactams is fundamentally important, but has rarely been studied, with the exception of reports on peptide-based lactams. Here, we find a consistent relationship between the trans/cis ratio of the lactam amide and the trans/cis-amide rotation rate upon elongation of the stapling side chain of two 7-azabicyclo[2.2.1]heptane bicyclic units linked via a non-planar amide bond. That is, as the chain length increases, the spinning rate from trans-to cis-lactam amide decreases, resulting in an increase in the trans ratio. This chain length dependence of lactam amide isomerization and our simulation studies support the idea that the current lactam amide can rotate 360 degrees due to the occurrence of nitrogen pyramidalization of lactam. The direction of tilting of the pyramidalization of nitrogen atoms in the bicyclic system is synchronous with the direction of the semicircular rotation of the amide.