Cyclic diketopiperazines

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 ... 

Going back to Miller s synthesis in the flask, one question is why a-amino acids have been obtained and not, for example, p-amino acids, cyclic diketopiperazines, or some other isomers. The answer is important a-amino acids form because they are the most stable products under the selected initial conditions. In other words the formation of those a-amino acids is under thermodynamic control. The same can be said for Oro s synthesis of adenine and other prebiotically low-molecular-weight substances formed in hypothermal vents, or found in space certain molecules and not others form because they are thermodynamically more stable. 

These rate constants were obtained through competition kinetics in D2O at pD 3.0-3.4, using isopropanol as a competitor. Several important features are noted (i) the cyclic diketopiperazines show generally higher rate constants per C-H bond compared to their linear analogs (cf, GlyA and N-Ac-Gly-NH2), (ii) the trend of calculated C-H bond energies does not match the trend of experimental rate... 

Figure 7.64 Cyclic diketopiperazines formed from proline and other amino acids contribute to the bitter taste of coffee.

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

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]. 

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). 

Incorporation of the Third Protected Amino Acid to Circumvent the Diketopiperazine Side Reaction That Occurs during Syntheses of Cyclic Peptides (R1 = C02Allyl) (Note 15)... 

To circumvent diketopiperazine side reactions that occur during syntheses directed at cyclic peptides and peptide... 

The cyclic dipeptides or diketopiperazines (DKPs) 6-10 are yet another class of small diffusible signal molecules that has been isolated from the culture supernatants of R aeruginosa, Pseudomonasputida WCS 358 and other Gramnegative bacteria. Their role in cross-talk with AHL-dependent QS has been demonstrated but their physiological function is not known [20,21]. 

Cyclic dipeptides are heterocyclic compounds comprising of two amino acid residues linked to a central diketopiperazine (DPK) ring structure. The general structure for DKPs can be seen in Figure... 

Table 1 Some naturally occurring simple cyclic dipeptides in the protist and plant kingdoms Diketopiperazine (all amino acids are in the L-configuration) Species...

We have previously seen how cyclic lactams can be synthesized by installing a protected amine in one of the Ugi or Passerini components, followed by cyclization onto the isocyanide-derived amide, taking advantage of the particular reactivity of convertible isocyanides. The same type of compounds can be accessed through nucleophilic attack of the amine onto an ester moiety, suitably installed as additional function into another component. This strategy has been widely used for the preparation of diketopiperazines 104 (Fig. 22), a typical privileged structure, starting with... 

Diketopiperazines (DKPs) are the smallest naturally occurring cyclic peptides. They are folded head-to-tail and conformationally constrained by a six-membered ring with the side chains orientated in a spatially defined manner. The DKP core... 

Excellent reviews covering the enantioselective synthesis of non-proteinogenic amino acids via metallated his-lactim ethers of cyclic dipeptides (2,5-diketopiperazines) (187) have been compiled by Schollkopf188). 

Esters of amino acids also cyclize, but they do so intermolecularly to give diketopiperazines. These compounds are cyclic amides ... 

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