Effect of copper(II) chloride on suppression of racemization in peptide synthesis by the carbodiimide method

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Abstract
Copper(II) chloride was found to be an extremely efficient racemization‐suppressing additive in the DCC method as compared with the hitherto known ones, by employing the model coupling Z‐Gly‐l‐Val‐OH +h‐l‐Val‐OMe in DMF. Although some other copper salts also had a profound effect, copper(II) chloride was the best from the viewpoint of both racemization suppression and coupling efficiency. The effectiveness of copper(II) chloride was further confirmed by employing the EDC‐mediated couplings of Z‐Gly‐containing dipeptides with amino acid esters or dipeptide esters, and those of Z‐l‐Ala (or l‐Val)‐l‐Val‐OH with amino acid esters or dipeptide esters. In almost all the cases studied, no detectable amount (< 0.1 %) of epimer was observed by the HPLC analysis in the presence of copper(II) chloride. This was also the case even with an extremely stringent coupling system Z‐l‐Pro‐l‐Val‐OH + H‐l‐Pro‐OMe. With reference to the mechanism of racemization suppression, it was found that copper(II) chloride has a strong ability to suppress the racemization of the 5(4H)‐oxazolone, which may be formed from an activated carboxyl component during the coupling.