The cis‐trans isomerization of N ‐methyl‐α,β‐dehydroamino acids

Dehydroamino acids with the methylated N ‐terminal peptide group occur in natural small cyclic peptides. The structural analysis was used to investigate the cis‐trans isomerization of the N ‐terminal tertiary amide group of diamides: Ac‐( Z )‐Δ(Me)Abu‐NHMe ( 1 ), Ac‐( Z )‐Δ(Me)Phe‐NHMe ( 2 ), Ac‐( E )‐Δ(Me)Phe‐NHMe ( 3 ), Ac‐Δ(Me)Ala‐NHMe ( 4 ), and Ac‐(Me)Ala‐NHMe ( 5 ). The compounds were analyzed in the solid state by an X‐ray crystallography ( 1 – 3 ), and in the solution by FTIR (MeCN and CHCl 3 ) and NMR (DMSO‐d6 and CDCl 3 ) methods ( 1 – 5 ). In the solid state, the studied compounds adopt the cis configuration of N ‐terminal amide. In solution, this configuration also prevails for the dehydroamino acids 1 – 4 , in contrast to the saturated analog 5 . The results indicate that N ‐methyldehydroamino acids present a promising tool to induce the cis configuration of the amide bond. © 2012 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 98: 466–478, 2012.