Racemization in Peptide Synthesis

This chapter discusses the racemization in peptide synthesis. Epimerization at the amino acid α-carbon has plagued the field of polypeptide synthesis throughout its history, placing severe constraints on the development of satisfactory synthetic routes to these molecules. Percentages or rates of exchange of hydrogen isotopes at the α-carbon of an aminoacyl derivative can be equated with racemization rates or percentages provided it can be shown that loss of chirality at this site occurs at the same rate as exchange. It is found that if the α-hydrogen is not isotopically homogeneous, kinetic isotope effects on enolization rate are expected and can lead to misleading rate discrimination. Several peptide derivatives have been demonstrated to exhibit the phenomenon of isoracemization, racemization rates exceeding those for exchange by as much as twentyfold. Racemization of amino acids under strongly acidic aqueous conditions is particularly pertinent to the behavior of amino acids under the conditions used for protein and peptide hydrolysis, prior to amino acid analysis. Racemization of amino acids under basic conditions has long been noted to be a relatively rapid process, particularly with amino acids that bear electron-withdrawing or α-conjugating substituents.