Fine-tuning the balance between peptide thioester cyclization and racemization

Ring-closure towards seven-membered bislactams containing an -amino acid and -alanine is problematic. Such difficult lactamizations are accompanied by side-reactions such as hydrolysis, oligomerization and racemization. By starting from linear peptide 4-methoxythiophenol esters, dilution to 1 mM in combination with phosphate buffer (pH 6.8) intermolecular reactions and racemization could be largely suppressed. Thioesters with the chiral residue at the C-terminus gave the bislactams in yields up to 60% and enantiomeric excess up to 99%. Enantiopure bislactams were obtained exclusively from the reversed sequence bearing -alanine at the C-terminus.