2.5- Diketopiperazines

A variety of metabolites, isolated from fungi or actinomycetes, displays a diketopiperazine ring [as (7.22)] in modified form, e.g. echinulin 7.24). (A related system is found in the benzodiazepines, see below.) The diketopiperazine metabolites can be seen as arising by combination of two a-amino acid residues through amide (peptide) linkages in the case of echinulin these amino acids are tryptophan (7.25) and alanine (7.25), and the diketopiperazine (7.22) is also a precursor for 7.24). 

The remaining, obviously isoprenoid, atoms in echinulin have been shown to arise from mevalonate in Aspergillus sp., as expected. Dimethylallyl pyrophosphate would follow as the source of the three isoprenoid residues and it has been found that a partially purified enzyme preparation from A. amstelodami would catalyse the transfer of an isoprene unit from dimethylallyl pyrophosphate (7.27) to (7.22) to yield (7.25) this compound was then found to be an intact precursor for echinulin 7.24). Prenylation of C-2 thus occurs before prenylation of the other two sites in echinulin biosynthesis [13, 14]. 

A similar pathway is deduced to lead to brevianamide A (7.55), in Penicillium brevicompactum, from tryptophan (7.25) and proline through the diketopiperazine (7.25), which has been isolated from P. brevicom-pactum. A further intermediate may be the Aspergillus ustus metabolite 7.29) (cf. echinulin biosynthesis) [15]. 

Mycelianamide (7.52) is a diketopiperazine formed from tyrosine (7.57) rather than tryptophan. However, the appropriate 

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The synthesis described met some difficulties. D-Valyl-L-prolyl resin was found to undergo intramolecular aminoiysis during the coupling step with DCC. 70< o of the dipeptide was cleaved from the polymer, and the diketopiperazine of D-valyl-L-proline was excreted into solution. The reaction was catalyzed by small amounts of acetic acid and inhibited by a higher concentration (protonation of amine). This side-reaction can be suppressed by adding the DCC prior to the carboxyl component. In this way, the carboxyl component is "consumed immediately to form the DCC adduct and cannot catalyze the cyclization. 

Formation of Diketopiperazines. Esters of a-amino acids can be readily prepared by refluxing anhydrous alcoholic suspensions of a-amino acids saturated with dry HQ. Diketopiperazines are formed by heating the alcohohc solution of the a-amino acid ester. 

Alitame (trade name Adame) is a water-soluble, crystalline powder of high sweetness potency (2000X, 10% sucrose solution sweetness equivalence). The sweet taste is clean, and the time—intensity profile is similar to that of aspartame. Because it is a stericaHy hindered amide rather than an ester, ahtame is expected to be more stable than aspartame. At pH 2 to 4, the half-life of aUtame in solution is reported to be twice that of aspartame. The main decomposition pathways (Fig. 6) include conversion to the unsweet P-aspartic isomer (17) and hydrolysis to aspartic acid and alanine amide (96). No cyclization to diketopiperazine or hydrolysis of the alanine amide bond has been reported. AUtame-sweetened beverages, particularly colas, that have a pH below 4.0 can develop an off-flavor which can be avoided or minimized by the addition of edetic acid (EDTA) [60-00-4] (97). 

Acid chlorides are useful reagents, but when the pyrazole is N- unsubstituted a dimerization occurs and the diketopiperazine (254) is isolated (Section 4.04.2.3.3(x)). However, (254) reacts with many compounds as an acid chloride would, for example with amines to yield amides (67HC(22)l). The difunctional pyrazole derivative (441) affords polymers by reaction with diphenols (69RRC763). Cyanopyrazoles can be hydrolyzed to the corresponding carboxylic acids (68CB829). 

Free-radical reactions in the synthesis of diketopiperazines and other cyclic derivatives of a-aminoacids 97CRV53. 

Another acylated ampicillin derivative with expanded antimicrobial spectrum is piperacil1 in (19). Its synthesis begins with 1-ethyl-2,3-diketopiperazine (j7, which itself is made from ]i-ethylethylenediamine and diethyl oxalate), which is activated by sequential reaction with trimethylchlorosilane and then trichloromethyl chioroformate to give This last... 

Treatment of an tr-amino acid with DCC yields a 2,5-diketopiperazine. Propose a mechanism. 

Similar reactions between diketopiperazine and either trialkyl phosphites or alkyl phosphinates produced the related cyclic analogs 17 and 18 (24). 

Several cyclic glyphosate analogs related to this series were described previously as intermediates to prepare glyphosate. These include various N-phosphonomethylhydantoins and diketopiperazines. A more extended glyphosate piperazine analog 106 has also been prepared firom the Mannich reaction of ethylenediamine-lV,lV -diacetic acid (65). 

Cyclic structures can form as a result of side reactions. One of the most common examples is the formation of diketopiperazines during the coupling of the third amino acid onto the peptide chain (Fig. 7). Intramolecular amide bond formation gives rise to a cyclic dipeptide of a six-membered ring structure, causing losses to the sequence and regeneration of the hydroxyl sites on the resin. The nucleophilic group on the resin can lead to fiuther unwanted reactions [14]. 

The property of thermal, reversible gelation is obtained by the addition of water-soluble proteins and protein degradation products to an aqueous solution of poly (vinyl alcohol) 2). Protein products such as albumin, gelatin, glue, a-amino acids, and their condensation products—diketopiperazines—may be used. A typical formulation for the preparation of a thermally reversible gel is ... 

Marsden BJ, Nguyen TM-D, Schiller PW. Spontaneous degradation via diketopiperazine formation of peptides containing a tetrahydroisoquinoline-3-carboxylic acid residue in the 2-position of the peptide sequence. Int J Peptide Protein Res 1993 41 313-316. 

N. ..N axes parallel to each other) with the trityl groups in contact and the space between the diketopiperazine rings filled by methylene chloride. In the resulting structure every guest moiety is within pseudo-cage-type voids surrounded by four adjacent hosts, representing lattice inclusion which is not assisted by any specific coordination between host and guest. 

Not surprisingly, the diacid 13 and its diamide are waterlogged with 2-4 molecules of HzO from which they are difficult to liberate. Binding experiments in CHC13, a non-competing solvent, revealed that stoichiometric complexes, e.g. 48 were formed with diketopiperazines 40) (Kh 104) and amides such as malonamide. With structures of inadequate hydrogen bonding capacity, such as sarcosine anhydride, com-plexation does not occur. 

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. 

Scheme 9.11. Synthesis of 2,5-diketopiperazines 9-57 and 1,4-benzoazepine-2,5-diones 9-58 by an Ugi-4CR process.

In this context it must be mentioned that the procedure by Kennedy and coworkers, in which a novel resin-bound isonitrile is applied in an Ugi multicomponent reaction for the synthesis of 2,5-diketopiperazines and 1,4-benzodiazepine-2,5-diones, was discussed earlier, in Chapter 9. 

The question of the stability of the biomolecules is a vital one. Could they really have survived the tremendous energies which would have been set free (in the form of shock waves and/or heat) on the impact of a meteorite Blank et al. (2000) developed a special technique to try and answer this question. They used an 80-mm cannon to produce the shock waves the shocked solution contained the two amino acids lysine and norvaline, which had been found in the Murchison meteorite. Small amounts of the amino acids survived the bombardment , lysine seeming to be a little more robust. In other experiments, the amino acids aminobutyric acid, proline and phenylalanine were subjected to shock waves the first of the three was most stable, the last the most reactive. The products included amino acid dimers as well as cyclic diketopiperazine. The kinetic behaviour of the amino acids differs pressure seems to have a greater effect on the reaction pathway than temperature. As had been recognized earlier, the effect of pressure would have slowed down certain decomposition reactions, such as pyrolysis and decarboxylation (Blank et al., 2001). 

If longer peptides are to be synthesized, the dipeptides as well as the monomers must be activated. This leads to a side reaction which can endanger the required chain-forming reaction, the formation of cyclic diketopiperazines ... 

The stepwise polymerisation of activated amino acids leads to the formation of activated dimers, which very often cyclise to diketopiperazines and are thus removed from the chain elongation process (Orgel, 1989). 

However, in the presence of COCI2, the amino acids are converted to cyclic anhydrides, which are referred to in peptide chemistry as Leuchs anhydrides . These polymerize in aqueous media to give peptides, without the formation of larger amounts of diketopiperazines (Brack, 1982). 

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