2,5-Piperazinedione ring

Throughout this article, the heteroring will be referred to as either piperazine-2,5-dione or occasionally as cyclodipeptide. The earlier practice of referring to the ring as diketopiperazine has been avoided. The numbering of the piperazinedione ring is as shown in (1). In the cyclodipeptide nomenclature, the common three-letter code for the two amino acids, with the necessary prefix to indicate absolute configuration, will be used. 

Other cyclodipeptides incorporating a proline and another aliphatic amino acid possessing a rm-butyl group have been investigated by Blaha and co-workers (87CCC2295). The f-butyl group helps to flatten the boat conformation of the piperazinedione ring. 

The conformation of cyclodipeptides containing two nonidentical l-aromatic amino acid residues has been addressed recently [90JCS(P2)127]. In such cases, it may be possible to assess the relative strength of the attractive interaction between the piperazinedione ring and the different aromatic groups by NMR studies. On the basis of detailed analyses, the author has concluded that in the case of cyclo[L-5(MeO)Trp-L-Tyr(Me)], a fast conformational equilibrium exists between the two folded-extended conformers (Scheme 10) above room temperature in DMSO and N,N-dimethyl formamide (DMF) solutions. 

Nucleophilic displacement of other functionalities Displacement of bromide by thiolacetate was one of the earliest successful methods for the introduction of a sulfur substituent on the piperazinedione ring (68BBR402). It was subsequently found that treatment of 3,6-dibromo-l,4-dimethylpiperazine-2,5-dione (115) with methanolic methanethiolate... 

Acidity of the methines A new method of constructing complex piperazine-2,5-diones with a disulfide bridge was first described by Kishi and co-workers (73JA6490 81T2045). The key is the introduction of substituents on the piperazinedione ring after the sulfur atoms have been installed. Regiospecificity is ensured by the significant difference in the acidities of the two methines. 

Sporidesmin is a naturally occurring polycyclic disulfane that contains the piperazinedione ring shown in Table 6. The corresponding trisulfane has been termed sporidesmin E. It has been obtained by extraction of Pithomyces chartarum followed by LC on silica gel. From the same organism, sporidesmin G, the corresponding tetrasulfane, has been obtained. These compounds are also biologically active. 

The D-amino acid subunits of a cyclopeptide are not incorporated as such, but are formed by inversion of configuration within the peptide chain. It seems plausible to assume that this inversion takes place in the piperazinedione ring or in the cyclopeptide via a dehydroamino acid intermediate. 

Facile inversion of amino acid subunits in the piperazinedione ring is frequently observed. Furthermore, the stability of the /ram-piperazinediones is in many cases greater, making possible the formation of an L-D-cyclopeptide from an L-L-cyclopeptide under thermodynamic control. 

Preparation of diketopiperazine as part of a bicyclic system was developed by a one-pot Ugi-4-center-3-component reaction (U-4C-3CR) [50]. A 3-keto or aldo acid 155 was used as bifunctional educt for an intramolecular Ugi reaction forming a five-membered ring. The application of C-protected amino acids 156 as amine components enables an intramolecular cyclization forming 2,6-piperazinediones 158 (Scheme 26). 

Hydrogenolytic N-deprotection of (17) led to piperazinedione (18) by opening the azetidinone ring (84T1039)... 

An extremely interesting extension of this method has led to the synthesis of monoethers of piperazinediones (88JOC5785), which are not otherwise easily accessible. The dichloroacetyl derivative (22) of the glycina-mide (21) undergoes base-catalyzed condensation with alcohols to give the piperazinediones (23). This has been used to generate bicyclic [n.2.2] piperazinediones in which the second ring is created by C—C bond formation. Thus, the butenediol derivative (24) obtained by the procedure out-... 

As explained in a later section (Section VII) cyclodipeptides, especially those containing histidine residues, have been used as synthetic enzyme mimics. Three different aspects of the cyclodipeptide molecular architecture have been made use of in achieving those results (a) H-bond formation with one of the NH groups of the piperazinedione (b) stacking of the aromatic ring over the hetero ring due to weak attractive forces, and (c) hydrophobic interactions with aliphatic side chains. 

Cyclizations involving bond formation between N-1 of the piperazinedi-one and C-2 of the indole ring of tryptophan have been reported. A few cyclodipeptides incorporating tryptophan have been shown to undergo cyclization in acid medium. The mechanism probably involves initial /3-protonation followed by addition of the piperazinedione to the iminium ion (85CPB4783) (Scheme 13). 

Cyctization of piperazinediones. An efficient synthesis of the unusual ring system (3) of the antibiotic bicyclomycin is based on treatment of a protected piperazinedione (2) with 2.0equiv. of 1 at 25°. The reagent effects deprotection of the silyl group and removal of the pyridylthio residue prior to cyclization to give 3 in 90-99% yield in 2-3 minutes. The same overall transformation can be effected by treatment first with the HF-pyridine complex and then with AgC104 in yields of 60... 

Fluorous aminoesters have also been used in DOS of three unique triaza tricyclic and tetracyclic ring systems (Scheme 22) [44], Bicyclic pyrrolidines 12 generated from one-pot, three-component 1,3-dipolar cycloaddition of azomethine ylides were further converted to hydantoin-, piperazinedione-, and benzodiazepine-fused compounds 31-33, respectively. Each of these three heterocyclic scaffolds has four stereocenters on the central pyrrolidine ring and up to four points of diversity (R1 to R4). The structure of compound... 

W. Zhang, Y. Lu, C. H.-T. Chen, D. P. Curvan, and S. Geib, Fluorous Synthesis of Hydrantoin-, Piperazinedione-, and Benzodiazepinedione-Fused Tricyclic and Tetracyclic Ring Systems, Eur. J. Org. Chem. (2006), 2055-2059. 

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