2,3-Piperazinediones

Several earlier methods (55,56) utilized a piperazinedione derivative in an Arbuzov-based sequence as a more stable source of the requisite iV-chloromethyl intermediate 51. Treatment of piperazine-1,4-dione with formaldehyde and phosphorus trichloride provided convenient access to this starting material. Subsequent reaction with either trimethyl or triethyl phosphite produced the iV-phosphonomethyl tetraester derivative 52, which has been hydrolyzed to GLYH3. 

JC Purdie, NL Benoiton. Piperazinedione formation from esters of dipeptides containing glycine, alanine and sarcosine the kinetics in aqueous solution. J Chem Soc Perk Trans 2, 1845, 1973. 

H. Bundgaard, J. Hansen, Nucleophilic Phosphate-Catalyzed Degradation of Penicilloyl Phosphate Intermediate and the Transformation of Ampicillin to Piperazinedione , Int. J. Pharm. 1981, 9, 273-283. 

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). 

Leach CA, Liddle J, Peace S, Philp J, Smith lED, Terrell LR, Zhang J (2006) Preparation of l,6-disubstituted-(3R,6R)-3-(2,3-dihydro-lH-inden-2-yl)-2,5-piperazinedione derivatives as oxytocin receptor antagonists for the treatment of pre-term labor, dysmenorrhea and endometriosis. PCT Int Appl WO 2006067462 Al 20060629... 

Ugi I, Horl W, Hanusch-Kompa C, Schmid T, Herdtweck E (1998) MCR 6 chiral 2, 6-piperazinediones via Ugi reactions with alpha-amino acids, carbonyl compounds, isocyanides and alcohols. Heterocycles 47(2) 965-975... 

Stereoselective formation of 3-alkyl-6-methoxy-2,5-piperazine-dione derivatives by the addition of methanol in the presence of NBS to 3-alkyl-6-alkylidene-2,5-piperazinediones was recently reported by Shin et al. 232 The asymmetric induction in this reaction was accomplished by the chiral center of a derivative of the natural proteinogenic chiral amino acid threonine. 

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. 

It is well known that derivatives of a-amino acids, especially the esters, can undergo cyclodimerization to form piperazine-2,5-diones. The stereochemistry of such self-condensation of initial stages but increasing amounts of the trans product were formed later. The results have been interpreted as reflecting the difference in the rates of cyclization of the two diastereomeric dipeptide esters. 

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

The azalactones (19) obtained by the Ugi condensation, on thermolysis, give the piperazinediones (20) in almost quantitative yields [73AG(E)79]. 

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-... 

This is a general method, leading to either 3-hydroxypiperazine-2,5-diones, or to the corresponding alkylidene derivatives (74CB2804). Thus A-pyruvoylproline methylamide cyclizes in water at pH 7.5 to yield the piperazinedione the cyclization appears to be highly stereoselective, leading to the kinetically controlled product (26). The scope of the method has been considerably expanded by Dutch workers, who have used it for the synthesis of l-hydroxypiperazine-2,5-dione derivatives (see Section VI). 

An extremely interesting and novel method has been described (91TL133). The principle involved is the intramolecular Diels-Alder addition of a 2,4-dienoic acid amide with an azodicarbonyl moiety. /V-Sorbyl-proline (27) was condensed with an acylhydrazine to form (28). Oxidation of this with lead tetraacetate (LTA) in boiling benzene resulted in the piperazinedione (30). This must have come about via (29), which could undergo an intramolecular Diels-Alder reaction. The structure and stereochemistry of (30) were confirmed by X-ray crystallography. The two new chiral centers have the R configuration as shown in (Scheme 9). 

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. 

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). 

Oxidative cyclizations of cyclodipeptides incorporating tryptophan have also been reported (81TL5323). Thus, irradiation of the piperazinedione (39) in formic acid in the presence of a sensitizer such as proflavine or chloranil gave the hydroxypyrroloindole (40). Oxidation with thallium (III) trifluoroacetate gave the dimer (41) in 3% yield. 

Cyclol formation on both carbonyl groups of the piperazinedione has been utilized for the synthesis of cyclotetradepsipeptides (Scheme 18). This strategy has been employed in the synthesis of serratamolide. 

Cyclization of the dipeptide and cyclol formation can be carried out in a single step (90MI1). The substrate in this case was the p-nitrophenyl ester (-ONp) of A-salicyloylphenylalanylproline. Treatment of this active ester (55) in benzene solution with DBU gave the oxacyclol (56) in 40% yield. It has been shown that this involves cyclization to the piperazinedione, epimerization of the proline C—aH and then cyclol formation. The l3C-NMR spectrum of the product shows only two carbonyl signals in addition, there is a signal at 102.38 ascribed to the quaternary carbon... 

A tetracyclic azacyclol (66) has been obtained from the p-nitrophenyl ester of the linear tripeptide prolylphenylalanylproline (81TL3671). However, the tripeptide active ester Phe-Pro-Pro-ONp with an altered sequence did not lead to the cyclol (66). This suggests that in the former reaction the piperazinedione (65) is an intermediate (Scheme 20). 

A similar result was obtained when the piperazinedione carried an N-sulfonyl group. Thus deprotection of the Af-carbobenzoxy taurine derivative (71) of cyclo(Phe-D-Pro) led to the 10-membered cyclic compound (73) via the cyclol (72) (89MI1). 

Cyclic dipeptides, especially when N-alkylated, undergo extremely fast epimerization (79JA1885). For example, cyclo(L-Pro-L-Phe) is rapidly converted to its diastereomer, cyclo(D-Pro-L-Phe) (80% conversion), by treatment with 0.5 N NaOH at 25°C for 15 min. This diastereomer is the one in which the proline residue has epimerized and not the more activated phenylalanine. CNDO/2 calculations seem to provide a rationale for this. It is not yet completely clear why such base-catalyzed epimerizations of piperazinediones are so easy the conformation of the molecule may play a role in this (79MI1). It is also worth noting that even in linear peptides, rm-amides of N-alkyl-amino acids, which consist of s-trans and s-cis rotamers of almost equal energy, are more prone to racemization than the sec-amides, which exist only in the s-trans configuration. Of course, the amide functions of piperazine-2,5-diones are obliged to assume the s-cis conformation. 

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