Diketopiperazines cyclic amino acid

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

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 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). 

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)... 

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... 

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. 

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 ... 

This initial observation by Inoue et al. triggered intensive research in this area. Most of the efforts were dedicated to structural variation of the catalyst and to elucidation of the catalytic mechanism. With regard to the former, the many structural variations produced mainly confirmed 1 as the optimum catalyst. Variation of the aromatic amino acids involved [25, 26], side-chain methylation and/or modification [27], N-methylation [28], etc., all afforded catalysts of lower selectivity. In contrast, incorporation of a-Me-Phe led to diketopiperazines of activity and selectivity comparable with those derived from non-methylated Phe (for example 1) [29]. Similarly, attachment to Merrifield-resin or polysiloxane polymers proved detrimental to the enantioselectivity of the Inoue-catalyst 1 [30, 31]. Upon incorporation into a silicon based sol-gel glass matrix, however, the excellent enantioselectivity of the cyclic peptide 1 is preserved, and separation of the spent catalyst can easily be achieved by, e.g., filtration, centrifugation or simply decantation [32], Unfortunately, further catalytic cycles afforded much lower ee (ca. 30-35% max.) [32],... 

An alternative protocol towards pyrazino 2,l-b]quinazolines 79 relied on cyclocondensation of diketopiperazine-derived lactim ethers with anthranilic acid. Microwave dielectric heating in a domestic oven (600 W irradiation power) furnished heterocycles 79 within 3-5 min, while the corresponding reaction in an oil-bath required 2 hours heating at 120-140 °C [129]. The use of N-protected co-amino acids 83 in the microwave-assisted reaction with anthranilic acid 71 furnished pyrrolo 2, -b]quinazolines 85 via transannu-lar cyclization of the intermediate cyclic diamide 84 [126]. Subsequent in situ condensation with a variety of aldehydes furnished isaindigotone 86 and analogues, possessing cytotoxic activity (Scheme 51). 

This article deals with results achieved with the 2,5-dimethoxy-3,6-dihydropyra-zines, the heterocycles of type I. Results obtained with the imidazolinones III are discussed elsewhere 6). At first glance the heterocycles I look rather esoteric. However, the yare nothing but the bis-lactim ethers of the well known 2,5-diketopiperazines, the cyclic dipeptides. — At first, experiments with the symmetrical bis-lactim-ether (6) of cyclo(L-Ala-L-Ala) (5) are described and then results with several mixed bis-lactimethers. Symmetrical bis-lactimethers — i.e. those, build up from two identical amino acids — do have one disadvantage, inherent in the system, namely, only one half of the chiral auxiliary is recovered, the other half is incorporated in the product. But they are easily prepared and, hence, are good models to commence a study. 

Other reports for the boron-Mannich reaction include the synthesis of aminophenol derivatives,561 a-arylglycines,576 a growth hormone secretagogue NN703,577 a polyhydroxyindolizine alkaloid uniflorine A,578 and cyclic ct-amino acids.579 The reaction has been applied to solution-phase reactions580 and the solid-phase reaction581-585 for the synthesis of libraries of peptides, a-amino acids, and bicyclic diketopiperazines. The reactions were accelerated by the irradiation of microwave.586... 

Two functional groups in the molecule of amino acids offer the possibility of the formation of cyclic derivatives. On combining two molecules of the same amino acid, diketopiperazines are produced [264] (Scheme 5.25). With amido groups present in the... 

The procedure described is essentially that of Shioiri and Yamada.4 Diphenyl phosphorazidate is a useful and versatile reagent in organic synthesis.5 It has been used for racemlzation-free peptide syntheses,4 6 7 thiol ester synthesis, a modified Curtius reaction,6 9 10 an esterification of a-substituted carboxylic add,11 formation of diketopiperazines, an alkyl azide synthesis,13 phosphorylation of alcohols and amines,14 and polymerization of amino acids and peptides.15 Furthermore, diphenyl phosphorazidate acts as a nltrene source3 and as a 1,3-dipole.16 17 An example In the ring contraction of cyclic ketones to form cycloalkanecarboxyllc acids 1s presented 1n the next procedure, this volume. 

Likely products of step 2, precipitates of Zn or Ca salts of amino acids valine and isovaline, were subjected to heating to 320°C in a nitrogen atmosphere (Strasdeit et al. 2001), causing complete thermolysis. Besides the simple diketopiperazines (cyclic dipeptides) and other peptides, heterocyclic compounds arise, and ketones (namely, the symmetrical Ruzicka products which form from Ca salts after desamination of the amino acids, like 2,8-dimethylnonan-5-on) and other prebiotically feasible small molecules. As might be anticipated, product yields and distribution sensitively depend on whether Zn or Ca ions were involved. There is some quite simple precondition for... 

In Dickey s 1949 paper [24], he presented the idea that specific catalysis, analogous to that of enzymes, was a possible application for silicas imprinted against selected reactants or products. This idea does not appear to have been realised until 1962, when the group of Patrikeev demonstrated what could be regarded as an early synthetic enzyme [27]. The reaction studied was the polycondensation of amino acid esters, a reaction known to yield both linear polypeptides (4%) and cyclic peptides (diketopiperazine, 96%) (Fig. 1.7). 

The influence of a surface on the course of a polymerization reaction was discussed by Carothers (69) in 1936. He pointed out that in bulk solution the amino acids or their esters polymerize mainly to the cyclic dimers, the diketopiperazines. In living cells, however, these cyclic compounds are evidently not formed reaction is exclusively intermolecu-lar leading to the formation of linear polyamides. Carothers suggested that adsorption at a fat-water interface may well be responsible for this, since here the reactant monomer molecules will be oriented to lie flat in the plane of the surface. As an example, the molecule NH2 CH2-CO-NH-CHs COOH is anchored to the interface through the polar groups at each end and in the middle of the molecule. Under these conditions the difficulty of bending may prevent cyclization. 

This reaction liberates the free amino acid, glycine. If glycine is allowed to stand in solution, it reacts with itself to form a cyclic dehydration product called diketopiperazine ... 

The first synthesis of a siderophore was the preparation of ferrioxamine B over 20 years ago in order to confirm the chemical structure of this natural product67). Synthesis of the other hydroxamate containing siderophores has as a central problem preparation of the constituent to-N-hydroxy amino acid in an optically pure form. The most important such subunit in hydroxamate siderophores is Ns-hydroxy ornithine. This is a chiral building block of the diketopiperazine-containing siderophores (rhodo-torulic acid 68), dimerum acid 69), coprogen 70) and coprogen B 69>), the cyclic hexa-peptides of the ferrichrome family27), the fusarinines 71 -73) and the antibiotic ferri-chrome derivatives albomycines Sl5 S2 and e 61-62). 

One stoichiometric method that avoids the use of an expensive chiral auxiliary and allows for the use of nonpyrophoric bases is based on diketopiperazine chemistry. The use of this system as a chiral auxiliary is associated with a method that was developed for the preparation of the sweetener aspartame. At the same time, we were looking at the alkylation reactions of amino acid derivatives and dipeptides. These studies showed that high degrees of asymmetric induction were not simple, were limited to expensive moieties as the chiral units, and required the use of large amounts of lithium [25,26]. The cyclic system of the diketopiperazine has been used successfully by other investigators [27,28], and we also chose to exploit the face selectivity of this unit. L-Aspartic acid was chosen as the auxiliary unit because it is readily available and cheap. All of the studies were performed with sodium as the counterion because it is a more cost-effective metal at scale. Finally, we concentrated in the use of aldehydes rather than alkyl halides to allow for a general approach and so as not to limit the reaction to reactive alkyl halides. 

While equilibrium (3.29) for the uncatalyzed reaction of thiyi radicals with carbohydrates is located far to the left, the analogous equilibrium (3.30) with peptide and protein substrates may actually shift to the right-hand side. In equilibrium (3.30), the C radical of the amino acid moiety is displayed in a planar conformation in reality, this conformation may be approached in linear peptides by glycine (R=H) or cyclic peptide models, such as the diketopiperazines, but less likely by amino acid moieties different from glycine. 

Diketopiperazine (DKP), a cyclic dipeptide easily formed by the cyclodimerization of amino acid esters. The formation of diketopiperazines is an undesired cycliza-tion reaction by incorporation of the third amino acid by stepwise SPPS. The free amino group of the resin-bound dipeptide can attack the peptide-resin anchorage intramolecularly, resulting in the formation of diketopiperazine [J. R. Spencer etal., Int. J. Pept. Protein Res. 1992, 40, 282]. 

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