Piperazine-2,5-dione derivatives

Kinetic studies of the unnatural 6-a -epimer of ampicillin, fi-ept-ampicillin (154), have revealed an intramolecular process not undergone by ampicillin (or other natural /3-substituted penicillins) At pH 6-9, intramolecular attack of the jS-lactam carbonyl group by the side-chain amino group of (154) yields a stable piperazine-2,5-dione derivative (155). Theoretical calculations show that the intramolecular aminolysis of 6-epi-ampicillin nucleophilic attack occurs from the a-face of the -lactam ring with an activation energy of 14.4kcalmor In other respects, the hydrolysis of the b-a-epimer is unexceptional. 

A similar 3-(2-bromoethyl) derivative has been utilized to synthesize 1-aminocyclopropane-1 -carboxylic acid by an intramolecular base-catalyzed cyclization. This was possible when position 6 was blocked by the presence of two substituents. Some unexpected stereochemical results also came up in this study (85MI2). The starting material was the piperazine-2,5-dione derived from (/ )-(+ )-2-methyl-3-phenylalanine and glycine. The bislactim ether derived from this, on treatment with butyl lithium in THF at -78°C, gave the lithio derivative. Alkylation of this with 2-haloethyl... 

A solution of sulfur in dimethylformamide can act as an oxidant of certain A -blocked piperazine-2,5-dione derivatives, resulting in net dehydrogenation (1068). For example, (cis trans)-l,4-diacetyl-3,6-dibenzylpiperazine-2,5-dione (101) reacted with sulfur in dimethylformamide and triethylamine to form, after hydrolytic removal of the acetyl groups, 3-benzyl-6-benzylidenepiperazine-2,5-dione (102) (1968). Oxidation of 1,3,4,6-tetramethylpiperazine-2,5-dione (103) with lead tetraacetate in benzene gave 3,6-diacetoxy-3-acetoxymethyl-l,4,6-trimethylpiperazine-... 

The degradation products of cefactor - piperazine-2,5-dione derivative. 

For cephalosporins containing an amino group in the C7 side chain such as cephalexin, cephaloglycin, and cephradine, a polymerization can be imagined to occur by intermolecular aminolysis in the same way as the polymerization of am-picillin and other aminopenicillins. Such as reaction can, however, be expected to be much less effective for the cephalosporins since an autocatalyzed intramolecular aminolysis with the formation of piperazine-2,5-dione derivatives may occur to a much larger extent than an intermolecular aminolysis (Bundgaard 1976 c, d). 

Fig. 14. Time courses for ampicillin squares) a-aminobenzylpenicilloyl glucose solid circles) piperazine-2,5-dione derivative open dries), and a-aminobenzylpenicilloic acid triangles) in the reaction between ampicillin (1.55 x 0 M) and glucose (10% W/V) at pH 9.40 (0.2 M carbonate) and 22 °C. (Bundgaard and Larsen 1979)...

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. 

Linked piperazine-dione derivatives as heiicai mimetics for the disruption of bci-2-famiiy proteins... 

Pyridyl quinolone carboxylic acids, (V), and 7-piperazine quinazolin-2,4-dione derivatives, (VI), prepared by Park (5) and Domagala (6), respectively, exhibited broad-spectrum antibacterial activity with reduced cytotoxicity. 

Spectral studies on 1,4-dioxopyrrolo[ 1,2-alpyrazines abound. Infrared absorption properties of a variety of derivatives of 168 have been com piled,48,147 and related to the conformations of the piperazine-dione ring. Gas-chromatographic techniques for separating diastereo-meric mixtures of derivatives of 168 have been described.150 Mass spectral fragmentation patterns for a series of dioxopiperazines, including derivatives of 168, has been reported.151 Numerous nuclear... 

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>. 

The bromine atom of 4-aryl-2-(4-bromobutyl)-2,3,5,6,7,8-hexahydro-177- ancj -perhydropyrido[l,2-c]pyrimidine-l,3-diones was displaced with 4-substituted piperazines <2002FES959, 2004APH139, 2004PHA99>. Heating 3-hydroxymethyl derivatives of epimeric 6-methyl-l,3,4,6,7,llb-hexahydro-277-pyrimido[6,l-,2]isoquinolin-2-ones 152 resulted in the formation of the 3-unsubstituted derivatives 153 by loss of CH20 (Equation 26) <1997LA1165>. 

Amino-2-methoxyphenyl)perhydropyrido[l,2-tf]pyrazine was prepared from a 2-(5-nitro-2-methoxyphenyl)-3-one derivative by catalytic hydrogenation over Pd/C catalyst, followed by the reduction of the 3-oxo group by treatment with BH3-THF complex <1999WO99/042465>. A nitro group was reduced to an amino group in 2-[4-(3-nitrophenyl)piperazin-l-yl]butyl]perhydropyrido[l,2-tf]pyrazine-l,4-dione <2001JME186>, in 8-hydroxy-... 

The N-4-chlorobutyl benzodiazepine dione 221 (Scheme 46, Section 3.1.1.2 (1993MI249)) gives the piperazine derivative after amination with N-methyl piperazine. 

IV-acetyl pyrrolidines and -piperidines to the corresponding diones or ketones were similarly effected [405, 406], as were conversions of diacetyl and dibenzyl piperazines to diketo componnds by the same system (Table 5.1) [407]. Methylene groups adjacent to the N atom in tertiary polycyclic amines were oxidised by RuO /aq. NaCIO j/CCl (Fig. 5.5) [408]. A large-scale oxidation of l,4-bis(2-phenylethyl) piperazine to the dione was made by RnO /aq. Na(10 )/Et0Ac [409], and RuO /aq. Na(IO )/CCl converted dialkyl or diaryl A A -dimethyladenosines to the corresponding monoamido derivatives (Fig. 5.4) [410]. 

Studies with tryptophan and tyrosine derivatives and with tryptophan- or tyrosine-containing dipeptides or piperazine-2,5-diones (diketopiperazines, DKP) revealed structural moieties that affect the fluorescence quantum yield of these aromatic amino acids (for a review, see... 

Finally, ortho aminoesters have been used to produce 7-deazaxanthines. For example ethyl 2-amino-5-phenyl-l//-pyrrole-3-carboxylate is first treated with 2-chloroethyl isocyanate in refluxing toluene. The resulting urea derivative is then allowed to react with l-(2-methoxyphenyl)piperazine and cyclized to the expected pyrrolo[2,3-,7 pyrimidin-2,4(177,377)-dione <2006BMCL150>. 

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. 

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... 

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