Diketopiperazine dipeptides

Roasting cocoa beans results in the production of volatile and non-volatile compounds which contribute to the total flavor complex. 5-Methyl-2-phenyl-2-hexenal, which exhibited a deep bitter persistant cocoa note, was reported in the volatile fraction (53). It was postulated to be the result of aldol condensation of phenylacetaldehyde and isovaleraldehyde with the subsequent loss of water. The two aldehydes were the principal products of Strecker degradation products of phenylalanine and leucine, respectively. Non-volatiles contained diketopiperazines (dipeptide anhydride) which interact with theobromine and develop the typical bitterness of cocoa (54). Theobromine has a relatively stable metallic bitterness, but cocoa bitterness is rapidly noticed and disappears quickly. 

A further example of DMAPP alkylation is the A-prenylation of tryptophan in the biosynthesis of the cyclic peptides cyclomarin and cyclomarazine (diketopiperazine dipeptides) (Section 3.2.8) (Figure 1.13) [16]. 

Cyclomarazines A and B, which are diketopiperazine dipeptides, were isolated and characterized along with cyclomarin D (Section 3.2.8) from the marine bacterium Salinispora arenicola CNS-205 (Figure 5.47) [223]. Unnatural cyclomarazines M and P were isolated upon addition of A-(l-methyl)tryptophan and A-(l-propargyl)tryptophan, respectively, to a culture of S. arenicola cymD knockout mutant [224]. 

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. 

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]. 

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 most common bicyclic 5-6 system with one bridgehead N-O and one extra heteroatom described in the period covered in this chapter has been the diketopiperazine derived from proline as it is present in natural products, in biologically active synthetic molecules, and has been used as starting material for the preparation of conformationally constrained peptidomimetics. The classical approach to this class of molecule is the ring closing of the dipeptide derived from proline and another amino acid via nucleophilic attack of the NH2 to the activated carboxylic group. This method has been applied several times to prepare different diketopiperazines for different uses. 

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]. 

Several prenylated dipeptide methyl esters undergo rapid diketopiperazine formation upon N-terminal... 

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...

Synthesis of funtionalized (Z)-fluoroalkene-type dipeptide isosteres (36) via Sml2-mediated reduction of y,y-difluoro-ot, -enoates 2.3.19. Reductive formation of fluoroolefins and subsequent conversion to diketopiperazine mimics (71). Nonpeptidic amide bond replacement... 

Studies with tryptophan and tyrosine derivatives and with tryptophan- or tyrosine-containing dipeptides or piperazine-2,5-diones (diketopiperazines, DKP) revealed structural moieties that affect the fluorescence quantum yield of these aromatic amino acids (for a review, see... 

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). 

The principal pathway for the decomposition of aspartame begins with the cleavage of the ester bond, which may or may not be accompanied by cyclization (Fig. 2). The resultant diketopiperazine and/or dipeptide can be further hydrolyzed into individual amino acids (qv). 

Because cleavage from the support only occurs upon cyclization, most by-products formed during solid-phase synthesis of the dipeptide remain attached to the support, and the diketopiperazines obtained are usually very pure. 

This preparation is analogous to the formation of diketopiperazines from dipeptide esters. In a similar approach, morpholine-2,5-diones were obtained by acidolytic cleavage of N-(bromoacety 1)am ino acids from Wang resin (Entry 3, Table... 

In the literature there is also an example of an intramolecular Ugi reaction with dipeptides used as bifunctional components, via their amino and carboxy groups [78] (Scheme 1.29). The postulated mechanism for this reaction, leading to N-substituted 2,5-diketopiperazines, is a U-4C-3CR characterized by the formation of a nine-membered cyclic intermediate that evolves to diketopiperazines 86 via ring contraction. Despite the ring size, the configurations of the two Ca of the dipeptide have some influence on the newly generated stereocenter, and diastereomeric ratios up to 6 1 can be obtained. 

---