Synthesis of Constrained Peptidomimetics Containing 2-Oxo-1,3-oxazolidine-4-carboxylic Acids

Sulfonyl peptides containing a serine or threonine residue undergo cyclization with bis(succinimidyl) carbonate (DSC) and diisopropylethylamine (DIPEA) to give peptides with a 2-oxo-1,3-oxazolidine-4-carboxylate (Oxd) group, either in solution or in the solid phase. The position of the serine or threonine residue in the sequence is relatively unimportant. Under the same conditions, the corresponding Fmoc- or Boc-peptides gave dehydration products, in agreement to previous studies. The protocol constitutes a valuable approach to the preparation of oxazolidinone-containing peptides, which are a recently emerging class of constrained peptidomimetics. As a representative example, an Oxd analogue of the endogenous opioid peptide endomorphin-1, characterized by an all-trans conformation, was readily prepared.