Piperazine-2,6-diones reactions

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. 

Elimination reactions have more often been carried out with piperazine-diones containing suitable leaving groups (OH, acetoxy, SCH3) in positions 3 and/or 6. In some cases 102, 168) the hydroxy compound is not isolated, but loses water in situ. Starting compounds for elimination reactions are summarized in Table 2. 

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. 

Conjugate addition of azide ion to dihydropyran-2,5-diones affords the 3-amino derivative <96SL341>, whilst reaction with bisnucleophiles provides a route to piperazines, thiazines and diazepines <96JHC703>. 

Once it is part of a cyclic dipeptide, the prolyl residue becomes susceptible to enantiomerization by base (see Section 7.22). The implication of the tendency of dipeptide esters to form piperazine-2,5-diones is that their amino groups cannot be left unprotonated for any length of time. The problem arises during neutralization after acidolysis of a Boc-dipeptide ester and after removal of an Fmoc group from an Fmoc-dipeptide ester by piperidine or other secondary amine. The problem is so severe with proline that a synthesis involving deprotection of Fmoc-Lys(Z)-Pro-OBzl produced only the cyclic dipeptide and no linear tripeptide. The problem surfaces in solid-phase synthesis after incorporation of the second residue of a chain that is bound to the support by a benzyl-ester type linkage. There is also the added difficulty that hydroxymethyl groups are liberated, and they can be the source of other side reactions. 

Azetidones (p-lactams) are generally obtained in high yield from (3-halopropion-amides (Table 5.18) and the low yield from the reaction of N-phenyl (3-chloropropi-onamide can be reconciled with the isolation of A-phenyl acrylamide in 58% yield [34]. The unwanted elimination reaction can be obviated by conducting the cyclization in a soliddiquid system under high dilution [35, 36]. Azetidones are also formed by a predominant intramolecular cyclization of intermolecular dimerization to yield piperazine-2,5-diones, or intramolecular alkylation to yield aziridones. Aone-pot formation of azetidones in 45-58% yield from the amine and P-bromocarboxylic acid chloride has also been reported [38]. 

In contrast, liquidiliquid phase-transfer catalysis is virtually ineffective for the conversion of a-bromoacetamides into aziridones (a-lactams). Maximum yields of only 17-23% have been reported [31, 32], using tetra-n-butylammonium hydrogen sulphate or benzyltriethylammonium bromide over a reaction time of 4-6 days. It is significant that a solidiliquid two-phase system, using solid potassium hydroxide in the presence of 18-crown-6 produces the aziridones in 50-94% yield [33], but there are no reports of the corresponding quaternary ammonium ion catalysed reaction. Under the liquidiliquid two-phase conditions, the major product of the reaction is the piperazine-2,5-dione, resulting from dimerization of the bromoacetamide [34, 38]. However, only moderate yields are isolated and a polymer-supported catalyst appears to provide the best results [34, 38], Significant side reactions result from nucleophilic displacement by the aqueous base to produce hydroxyamides and ethers. 

Buspirone Buspirone, 8-[4-[4-(2-pyrimidyl)-l-piperazinyl]butyl]-8-azaspiro [4,5] decan-7,9-dione (5.2.6), is synthesized by the reaction of l-(2-pyrimidyl)-4-(4-aminobutyl)piperazine (5.2.4) with 8-oxaspiro[4,5]decan-7,9-dione (5.2.5). In turn, 1-(2-pyrimidyl)-4-(4-aminobutyl)piperazine (5.2.4) is synthesized by the reaction of l-(2-pyrimidyl)piperazine with 4-chlorobutyronitrile, giving 4-(2-pyrimidyl)-l-(3-cyanopropyl)piperazine (5.2.3), which is hydrogenated with Raney nickel into buspirone (5.2.4) [51-55]. 

Piperazine-2,5-diones can be symmetric or asymmetric. Symmetric DKPs are readily obtained by heating amino acid esters,1179-181 whereas asymmetric DKPs are obtained directly from the related dipeptides under basic or, more properly, acid catalysis, or by cyclocondensation of dipeptide esters.1182-185 As an alternative procedure hexafluoroacetone can be used to protect/activate the amino acid for the synthesis of symmetric DKPs or of the second amino acid residue for synthesis of the dipeptide ester and subsequent direct cyclocondensation to DKPs.1186 The use of active esters for the cyclocondensation is less appropriate since it may lead to epimerization when a chiral amino acid is involved as the carboxy component in the cyclization reaction. Resin-bound DKPs as scaffolds for further on-resin transformations are readily prepared using the backbone amide linker (BAL) approach, where the amino acid ester is attached to the BAL resin by its a-amino group and then acylated with a Fmoc-protected amino acid by the HATU procedure, N -deprotection leads to on-resin DKP formation1172 (see Section 6.8.3.2.2.3). 

B. Chiral Induction in Piperazine-2,5-dione-Catalyzed Reactions. 277... 

Symmetrical piperazine-2,5-diones have been obtained in good yields by treating Leuchs anhydrides (l,3-oxazolidine-2,5-diones) with aziridine [70AG(E)162]. The reaction apparently proceeds through the formation of dipeptide aziridides (Scheme 5). 

It has been known since 1921 that piperazine-2,5-dione can be condensed with benzaldehydes to form benzylidene derivatives (21CB163). However, the reaction needs drastic conditions and fails with aliphatic aldehydes. Gahina and Liberatori have introduced a significant improvement that permits the control of the reaction with aromatic aldehydes to obtain the monoarylidene derivatives it is also successful with aliphatic... 

Reaction of an enolate derived from piperazine-2,5-dione with an electrophilic sulfur species has been used to synthesize gliovictin and hyalo-dendrin. Thus, the enol (94) can be sulfenylated at low temperatures with sulfenyl chlorides in presence of triethylamine. A second thiomethyl group can be introduced at position 6 by reacting the enolate with dimethyldisul-fide as shown in Scheme 39. 

Displacement by nucleophiles C—C Bona formation has been accomplished by coupling the syn-3,6-bis(2 -thiopyridyl)piperazine-2,5-diones with ketene trimethylsilyl acetals in presence of silver triflate. There are several interesting features in this extremely useful reaction. The proce-... 

Piperazine-2,5-diones, in which both amino acid units are primary, lead to bislactim ethers on O-alkylation with Meerwein s reagents. No selectivity in this reaction has been demonstrated so far. Such bislactim ethers (171) have been prepared and extensively used by Schollkopf and his school [79AG(E)863, and later papers]. During the preparation of these bislactim ethers, neutralization of the initially formed bis-tetrafluoroborate salt is carried out with phosphate buffer to avoid racemization. 

A reaction of this kind has recently been carried out by Okawara et al.53,5 who have reported an efficient synthesis of piperazine-2,5-diones (22) via PTC cyclization of a-halocarboxamides (21). 

In analogy to proline dipeptides, A1-unprotected 2-carbonylpyrazolidine amino acid dipeptide esters 37 on storage at ambient temperature are prone to conversion into the related triazines 38 that correspond to the aza analogues of piperazine-2,5-diones (Scheme 5). 160 161 An additional side reaction is reported for the 2-azaproline peptides 161 which leads to formation of the cyclic imide 40 from methyl TV -lbenzyloxycarbonylj -carbonylpyra-zolidine glycinate (39) upon treatment with methanolic ammonia (Scheme 6). 

Boger and co-workers successfully used the intramolecular Ullmann reaction to prepare 23, an intermediate in their total synthesis of piperazinomycin (4) (Scheme 6). In this case, the C9 center of the piperazine-2,5-dione substrate did not epimerize, and the cyclization proceeded smoothly and in high yield 2 ... 

The spontaneous formation of piperazine-2,5-diones occurs mainly during N-deprotection or the acylation step to dipeptide esters (usually unhindered esters such as Me, Et, Bzl, and Pac esters) that contain an TV-alkyl amino acid especially at the C-terminusJ152 In some cases the formation of piperazine-2,5-diones becomes the major reaction product and thus prevents peptide elongation by the [1+2] or [1+3] segment condensation strategy in solution synthesis or elongation of the peptide from the C-terminus in SPPS. Piperazine-2,5-dione formation... 

This tripeptide was a key intermediate in an attempted preparation of c[3-(benzyloxymethyl)-2-nitrobenzoyl-Thr-D-Val-Pro-Sar-(Me)Val-] by the [2+3]-segment condensation strategy peptide and cyclization between Sar and (Me)Val. This side reaction was circumvented by using the dipeptide H-D-Val-Pro-OtBu in a [3+2]-segment condensation strategy. Contrary to its benzyl ester, this dipeptide did not form the piperazine-2,5-dione because of presence of the bulky tert-butyl ester.[165 1661 Cyclization was performed between Pro and Sar. 

The lability of peptides and proteins to acidic conditions was first reported in 1920 by Dakin,12031 who found that acid hydrolysis of peptides or proteins that contain consecutive N-alkyl amino acids leads to the formation of piperazine-2,5-diones (DKP) this side reaction lowered their yield during amino acid analysis. For example, the piperazine-2,5-dione c[-Hyp-Pro-] was isolated from the hydrolyzate of gelatine. 

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