cis-Amides and their periodicity

Molecular diversity is a term that is familiar to synthetic chemists. A diverse collection of molecules is characterized by a broad representation of functional groups, chemotypes, ring sizes, and so on. How do we judge how rich is the conformational diversity of a given collection? My lab’s efforts in the area of peptide macrocyclization have made me think quite a bit about this matter. It is particularly enticing to make big gains without too much synthetic effort.

Time and again, I look for papers that provide straightforward mechanisms of controlling accessible conformational space. In this regard, cyclic peptides offer an unprecedented opportunity, particulalrly once proline is considered. Proline is known for its relatively high barrier for cis/trans interconversion, which makes the X-Pro motif (X is an amino acid) an interesting structural feature to explore. A paper by Rabenstein and co-workers cited below provides a marvelous demonstration of capturing cis-amide bonds in disulfide macrocycles. The authors have found that the corresponding linear peptides contain Cys-Pro bond in its predominantly trans form. However, cyclic peptides display periodicity in cis/trans geometry of the Cys-Pro bond (marked red in the graphic below). It turns out that macrocycles containing an odd number of amino acid residues are predominantly cis at the Cys-Pro juncture, whereas those with an even number of amino acids are predominantly trans. This finding is significant as it offers a tool to sample various conformations by changing the number of residues in a macrocycle. I’m afraid the precise nature of this intriguing phenomenon is unknown.


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