Diketopiperazines, from amino acid esters

On the other hand, the esters of the polypeptides are of the greatest importance and they are prepared by the action of alcoholic hydrochloric acid. Hydrolysis of the polypeptide does not occur if prolonged heating be avoided, nor does hydrolysis occur when the esters are saponified by dilute cold caustic alkali. The esters have served in particular for the further synthesis of polypeptides and for the isolation of dipeptides from mixtures on treatment with alcoholic ammonia, the dipeptide esters are converted into their diketopiperazines. They are not soluble in petroleum ether and they are soluble with difficulty in ether, and they thus differ from amino acid esters. Chloroform dissolves them, and in this solvent their combination with acid chlorides has been generally effected. 

Diazines other than diketopiperazines can also be prepared on insoluble supports (Table 15.31 see also Figure 3.13 [382]). Most strategies are based on intramolecular nucleophilic substitutions or acylations. Several examples of the solid-phase preparation of quinoxalinones have been reported. In most cases, the compounds have been prepared from support-bound 2-fluoronitrobenzenes according to the strategies outlined in Figure 15.18. Alternatively, a-amino acid esters bound to polystyrene as IV-benzyl derivatives can be N-arylated with 2-fluoronitrobenzene. Reduction of the resulting 2-nitroaniline leads to the formation of quinoxalinones [383]. 1,4-Diazines have been chemically modified by N- or C-alkylation on insoluble supports (Entries 9 and 10, Table 15.31). 

For the preparation of the 2,5-diketopiperazines 9-57 and 1,4-benzodiazepine-2,5-diones 9-58, respectively, the isocyanide 9-54 was either treated with an aldehyde and an amino acid, or with an aldehyde and an anthranilic acid, to give either 9-55 or 9-56, using the conditions depicted in Scheme 9.11. Further transformations include liberation from the resin with KOtBu forming N-acyloxazolidones and treatment with NaOMe to afford the corresponding esters, which are then cy-clized to the desired products 9-57 and 9-58 under acidic conditions. 

The ester was prepared from and amino acid and the alcohol using DCC/DMAP. It was developed to prevent diketopiperazine formation during the formation and deprotection at the dipeptide stage of the growing peptide. It is cleaved with TBAF at approximately half the rate of TMSE cleavage." ... 

The hydrolysis of these compounds by the enzyme was determined by the isolation of the individual substances. The isolation of the amino acids soluble with difficulty in water, namely, tyrosine and cystine, presented no great difficulty, since those compounds crystallised out during the process of hydrolysis, but in the other cases the amino acids required separation from unchanged dipeptide. The ester method here again proved its usefulness the esters of the simple monoamino acids are easily volatile in vacuo and can be characterised by the methods previously described those of the dipeptides are not volatile and are characterised by conversion into their diketopiperazines or anhydrides by the action of ammonia, which compounds are less soluble than the dipeptides themselves and are thus capable of separation by filtration. 

The further attempts to again prepare this substance did not succeed, since the exact conditions leading to its formation could not be repeated, but in 1906 Fischer and Abderhalden obtained the anhydride of this body by a new method which they had discovered for isolating such compounds when mixed with amino acids and higher polypeptides. This method depends upon the different behaviour of the esters of these compounds those of the simple mono-amino acids are easily volatile in vacuo and are therefore easily removed, whereas those of the dipeptides are converted by the action of ammonia into their anhydrides or diketopiperazines which crystallise readily and are therefore easily separated from the esters of the higher polypeptides. They thus obtained a methyl diketopiperazine. 

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