Proline diketopiperazine formation

The main advantage of ferr-alkyl esters as linkers is their stability towards nucleophiles. For instance, no diketopiperazine formation is observed during the preparation of peptides containing carboxy-terminal proline, an otherwise common side reaction when using benzyl alcohol linkers (Section 15.22.1). 

The formation of the diketopiperazine ring from proline-containing peptides can occur in two ways (see type A and type B). Entropy considerations predict that type A syntheses should result in relatively easier cyclization than type B syntheses. In both approaches, the presence of a proline residue in the peptide allows ready cyclization to the diketopiperazine under conditions which would leave other nonproline-containing dipeptides unaffected. ... 

Treatment of the benzylidene compound 144 with sodium hydroxide or sodium acetate provides the expected proline derivative 145 but without concomitant deacetylation. The use of ammonia provides the corresponding proline amide. When compound 144 is treated with sodium leucinate, the ring opens at the alternative site and deacetylation occurs, resulting in the formation of the prolyldipeptide 146 and iV-acetylleucine. If sodium glycinate or ethyl glycinate is used instead, simple deacetylation takes place to give the diketopiperazine 147. Deacetylation may also be achieved with aromatic amines in chloroform at room temperature. A... 

With increasing use of Fmoc SPS, a number of base-mediated side reactions have been identified and reported that require careful awareness [61]. Some of these are described elsewhere in this volume (Chapters 2 and 4). The principal base-mediated side reactions are diketopiperazine formatioii caused by cyclization, particularly during A -deprotection of the residue adjacent to C-terminal resin-linked proline [62], and aspartimide formation, particularly at Asp-X residues [63,64]. The former can now be prevented by use of the substantially sterically hindered 2-chlorotrityl linker [65]. The latter side reaction is more difficult to control and appears to be largely sequence dependent. Asp-Gly, -Ser, -Thr, -Asn, and -Gin pairs are most at risk of potential imide formation, although several other Asp-X combinations have also been observed to cyclize [66,67]. For one sensitive peptide sequence, use of piperazine for A -deprotection eliminated this side reaction [68]. However, for another peptide, this base was ineffective (J Wade, unpublished). Reduction of the basicity of the piperidine solution by addition of... 

The assignment of the structures of the brevianamides A-E, five closely related diketopiperazine metabolites isolated from the mould Penicillium brevicompactum, was based partly on the results of biosynthetic studies and biogenetic considerations The presence of an indole unit and a diketopiperazine ring in the brevianamides suggested the possibility of the formation of these metabolites from L-tryptophan and L-proline (101) with the additional C5 unit in the molecules originating in mevalonate (102). Biosynthetic evidence to support this conclusion was obtained in the case of brevianamide A (105). Thus DL-3-[ CJ-tryptophan and L-U-[ C -proline were both readily incorporated into the... 

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