When it comes to making cyclic peptides, we have a tendency to recall all sorts of nightmares. Choosing the right protecting group and running reactions under high dilution in order to avoid polymerization are two of the most common sources of headaches. These are presumed headaches, I must add. We know that exceptions prove the rule and I fully admit that outliers in this field probably possess some very special features. The corresponding outlier peptide would stand out as a sore thumb, challenging widely accepted views and fears. This is therapeutic to all of us. A case in point is a solution phase reaction developed by Fairlie and co-workers some years ago. This cyclization is: a. not run at high dilution, b. not associated with protecting groups, c. run over 2 hours on a 100g scale, affording 33g of the desired product. So, next time you are performing your cyclization with a laundry list of precautions in mind, think of such outliers and do not fall victim to default assumptions that dominate this field.
I have seen a process-scale cyclization of a therapeutic peptide, I believe by Ferring Pharma, performed on a fully-deprotected peptide, in water at 0C, with diphenylphosphoryl azide and triethylamine
It will be interesting to know which peptide it was!