Peptide Thioimidates: Why Cis/Trans Stays ~50/50

Summary. Researchers at Iowa State University reported in Organic Letters, published online on 20 October, a systematic study of the structural factors that control isomerization of thioimidates in the peptide backbone. A thioimidate replaces the backbone amide with a carbon-nitrogen double bond carrying a sulfur substituent, and unlike a normal amide it often populates its trans and cis forms in nearly equal amounts. Thioimidates are increasingly used as intermediates for peptide backbone editing and macrocyclization, but the factors that govern this equilibrium had not been characterized.

Research context (RUO). The team combined NMR spectroscopy with density functional theory (DFT) calculations to measure the thermodynamics and kinetics of thioimidate isomerization in a series of model peptides. The near-equal trans/cis equilibrium, and the energy barrier between the two forms, proved largely insensitive to the steric bulk and stereochemistry of the amino acids on either side of the thioimidate. In contrast, increasing the steric demand of the substituent on the thioimidate sulfur produced the largest shift in the equilibrium, enriching the form tentatively assigned as cis, which suggests the sulfur substituent could be used to tune the balance. The calculations support an isomerization mechanism in which the nitrogen rehybridizes through a linear transition state, rather than direct rotation about the formal carbon-nitrogen double bond. The authors conclude that this sequence independence gives chemists considerable freedom in where thioimidates can be placed within a peptide, so that their dynamic conformational behaviour can be used broadly in peptide synthesis and macrocyclization. The paper is a physical-organic and synthetic-methods report with no biological or clinical testing. For peptide-chemistry laboratories, it provides baseline rules for predicting the conformational behaviour of thioimidate-modified backbones.