Piperazine-2,5-Dione Formation from Esters of Dipeptides

19 PIPERAZINE-2,5-DIONE FORMATION FROM ESTERS OF DIPEPTIDES 

FIGURE 6.24 The cis and trans forms of the amide bond of a dipeptide ester and cyclization of the compound to the piperazine-2,5-dione. The tendency to cyclize is greater when the carboxy-terminal residue is proline or an IV-methylamino acid. In these cases the predominating form is cis, which places the amino and ester groups closer together. 

Once it is part of a cyclic dipeptide, the prolyl residue becomes susceptible to enantiomerization by base (see Section 7.22). The implication of the tendency of dipeptide esters to form piperazine-2,5-diones is that their amino groups cannot be left unprotonated for any length of time. The problem arises during neutralization after acidolysis of a Boc-dipeptide ester and after removal of an Fmoc group from an Fmoc-dipeptide ester by piperidine or other secondary amine. The problem is so severe with proline that a synthesis involving deprotection of Fmoc-Lys(Z)-Pro-OBzl produced only the cyclic dipeptide and no linear tripeptide. The problem surfaces in solid-phase synthesis after incorporation of the second residue of a chain that is bound to the support by a benzyl-ester type linkage. There is also the added difficulty that hydroxymethyl groups are liberated, and they can be the source of other side reactions. 

Dioxopiperazine formation is avoided by esterifying the carboxy terminus of a chain with a tertiary alcohol, which provides a poor leaving group, tert-Butyl and 

HN Rydon, PWG Smith. Self-condensation of the esters of peptides of glycine and proline. J Chem Soc 3642, 1956. 

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