Diketopiperazine, structure

A comprehensive compilation of data derived from feeding and other biosynthetic studies performed by Kirby [21], Sammes [22], and Taylor [23], genomic studies conducted by Howlett [lc, 24], as well as our own synthetic studies probing the innate reactivity of various intermediates (vide infra) culminated in our formulation of the biosynthetic hypothesis delineated below (Scheme 9.1). The biosynthesis features two distinct phases an oxidative dimerization phase and a thiolation phase in which diketopiperazine structures are elaborated to afford the defining epipolysulfide motifs (Scheme 9.1) [25, 26]. 

In the 1970s, Kishi published a series of landmark papers [36] describing the total syntheses of ( )-dehydrogliotoxin (1973) [36b], ( )-sporidesmin A (1973) [36c], ( )-gliotoxin (1976) [36d], and ( )-hyalodendrin (1976) [36e] in which he employed a new method for epidithiodiketopiperazine synthesis (Scheme 9.4). Cognizant of the harsh conditions required in all of the sulfur incorporation methods developed at the time, it was determined that thiolation would be performed in the early stages of the syntheses. A dithiol intermediate obtained in a similar fashion to Trown s epidithiodiketopiperazine was protected as a dithioacetal, and after elaboration of this core diketopiperazine structure, the dithioacetal was unraveled under mild conditions in the final steps to afford the target epidisulfides. 

Dihydroxy derivative 277 when treated with sulfur monochloride provided in 65% yield sulfur-bridged diketopiperazine structure 298 (Scheme 73) (77JOC948). 

Fig. 4 Diketopiperazine structural isomers. Isomer 3 is the most relevant natural cyclodipeptide...

In the alternative Mannich route to the spiro intermediate 14, the indole ring of 4 is oxidized first. The resulting oxoindoline 11 is then converted by treatment with senecialdehyde (5, prenal ) into a mixture of four diastereomers of compound 12, which are acetylated, as a mixture, to 14. The two total syntheses differ with respect to the formation of the diketopiperazine structure and the introduction of the C8-C9 double bond of spirotryprostatin B (2), with quite divergent overall yields. 

Diketopiperazine formation has long been described as a side reaction in peptide synthesis. It occurs after deprotection or neutralization of the oc-amino group at the dipeptide stage and reduces the overall yield of the synthesis. However, diketopiperazine structures have also been found in natural products with therapeutic properties and hence they have been used as a scaffolds to design new potential drugs [38, 91, 92]. A typical example would be the synthesis of indolyl diketopiperazine alkaloids. Access to these compounds may be achieved by Pictet-Spengler reaction of L-tryptophan bound to hydroxymethylpolystyrene resin with aldehydes. Fmoc amino acids were then coupled and final Fmoc deprotection resulted in cyclative release to yield alkaloids in 50-99% yields (Figure 15.9) [93, 94],... 

Thus far, no evidence of a diketopiperazine b anion has been reported, possibly because of the role of basic residues (which are not amenable to negative mode ionization) in the formation of diketopiperazine structures. 

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]. 

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. 

The final method for constructing epidithiodiketopiperazine motifs relied on the nucleophilic thiolation of /V-acyliminium ions. Access to alpha-oxidized diketopi-perazine structures was central to this approach, and key developments were made in this regard. Schmidt first demonstrated the feasibility of this ionization approach in 1973 by conversion of proline anhydride to its diacetate using Pb(OAc)4 [42], Hydrolysis of the acetates, ionization of the hemiaminals with zinc chloride in the presence of hydrogen sulfide, and oxidation with iodine provided the epidisulfide of interest. In 1975, Matsunari reported access to alpha-methoxy diketopiperazines,... 

Dimeric structures are possible as exemplified by the leptosins, from a strain of Leptosphaeria (a fungus isolated from the marine alga Sargassum tortile). Some of these, e.g. leptosin A 11, may have up to 4 sulfur atoms across the diketopiperazine ring system.23 Various leptosins have antitumor and cytotoxic properties. 

While we are not aware of any systematic investigation of the conditions and structural factors that influence diketopiperazine formation, the literature contains a number of examples of such reactions. Thus, cyclo(His-Trp), a degradation products of LHRH (Fig. 6.16, Reaction c), is a secondary product formed after cleavage of the Glp-His bond. After an incubation of 90 d at neutral pH, cyclo(His-Trp), represented 4 and 10% of the breakdown products obtained at 37° and 50°, respectively [74],... 

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... 

Figure 1 General structure of a 2,5-diketopiperazine, where and represent the substituting amino acid residues.

Diketopiperazines 17 and ketopiperazines 19, which are important privileged structures, have been obtained by using various convertible isocyanides and by introducing the additional amino function, respectively, on the carboxylic [39] or amine component [33]. 

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... 

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