Dioxopiperazine

Dioxopiperazines are amongst the most ubiquitous of natural products (75FOR(32)57) and they are formally derived by the cyclodimerization of a-amino acids (69CCC4000) or their esters. A number of methods are available for their oxidation to the corresponding pyrazines. Treatment of 2,5-dioxopiperazines with triethyl- or trimethyl-oxonium fluorobor-ate followed by oxidation with DDQ, chloranil or iodine results in pyrazine formation, usually in high yields (Scheme 63) (72JCS(P1)2494). 

Dioxopiperazines have been converted into the corresponding dihydroxypyrazines by base catalyzed isomerization of the corresponding arylidene derivatives (Scheme 64) (70JCS(C)980), although this reaction appears to be limited to the synthesis of benzyl- or aryl-substituted benzylpyrazines. 

Most of the naturally-occurring pyrazine hydroxamic acids appear to be derived from valine, leucine and isoleucine, and biosynthetic studies by MacDonald and coworkers (61JBC(236)512, 62JBC(237)1977, 65JBC(240)1692) indicate that these amino acids are incorporated. However, it would seem that the logical intermediates, viz. the 2,5-dioxopiperazines such as (111) and (112), are not always incorporated. This does not rule out their intermediacy, as there may be problems such as low solubility or membrane permeability which prevent their efficient incorporation. An exception to these results was reported for pulcherrimic acid (113) (65BJ(96)533), which has been shown to be derived from cyclo-L-leu-L-leu which serves as an efficient precursor. 

Figure 10. Possibilities of degradation or polycondensation reactions of MAR Key a, MAP b, optical isomer c, DNP-alanine d, DNP-ethylamine e, 2-nitroso-4-nitroaniline f DNP-alanyl-(DNP) a amino-propanoate of methyl and g,l,4-bis(DNP)-3,6-dimethyl-2,5-dioxopiperazine. [(DNP) = 2,4-dinitro-...

The commercially available form of Aspartame is hemihydrate Form II, which transforms into hemihydrate Form I when milled, and a 2.5-hydrate species is also known [57,58]. XRPD has been used to study the desolvation and ultimate decomposition of the various hydrates. When heated to 150°C, both hemihydrate forms dehydrate into the same anhydrous phase, which then cyclizes into 3-(carboxymethyl)-6-benzyl-2, 5-dioxopiperazine if heated to 200°C. The 2.5-hydrate was shown to dehydrate into hemihydrate Form II when heated to 70°C, and this product was then shown to undergo the same decomposition sequence as directly crystallized hemihydrate Form II. 

Cyclic dipeptides also known as cyclo dipeptides, DKPs, 2,5-dioxopiperazines (DOPs), or dipeptide anhydrides. 

Dioxopiperazines are products of sometimes unwanted cyclizations of the N-terminal residues of di- and oligo-peptides and proteins. As a model for this process. 

There are very few reactions of real synthetic significance which proceed via condensation of two 1,3-electrophile-nucleophile species. Probably the most important of this latter type of reaction is the synthesis of pyrazines by self-condensation of an a-acylamino compound to the dihydropyrazine followed by aromatization (equation 132). The a-acylamino compounds, which dimerize spontaneously, are normally generated in situ, for example by treatment of a- hydroxy carbonyl compounds with ammonium acetate or by reduction of a-azido, -nitro or -oximino carbonyl compounds. Cyclodimerization of a-amino acids gives 2,5-dioxopiperazines (equation 133), many derivatives of which occur as natural products. Two further reactions which illustrate the 1,3-electrophile-nucleophile approach are outlined in equations (134) and (135), but su i processes are of little general utility. 

Dioxane behaves as an acetal, 1,4-dioxane as a bis-ether, and 2,5-dioxopiperazine (538) as a bis-lactam. 

Dioxane behaves as an acetal, 1,4-dioxane as a bis-ether, and 2,5-dioxopiperazine 581 as a bis-lactam. Piperazine 582 (Z = NH) and morpholine 582 (Z = 0) show typical aliphatic secondary amine properties, but their pAa values, 9.8 and 8.4, respectively, (cf. piperidine pAa 11.2) reflect the inductive effect of the second heteroatom. 

Streptomyces pathogens are quite rare in plant diseases. Thaxtomin A from Streptomyces scabies causes scab disease of potato, which is characterized by conspicuous corky lesions on tubers. Molecular genetic investigation has revealed that thaxtomins are biosynthesized by nonribosomal peptide synthetases (txtAB) that condense modified L-phenylalanyl and L-4-nitrotryptophanyl units to form a 2,5-dioxopiperazine skeleton.316 Disruption of txtA results in the formation of nonpathogenic strain. This toxin is shown to affect the movement of calcium ions and protons across the plasma membrane and also inhibit cellulose biosynthesis.317... 

Originally H-T5ir(tBu)-OMe was prepared as the free base, which has to be used immediately after preparation because of 2,5-dioxopiperazine formation " however, it is stable as the HCl salt. ... 

Piperazine-2,5-dione treated with sodium hydride in A,A-dimethylacetamide and carbon disulfide followed by esterification with methyl iodide gave l-methylthio(thio-carbonyl)piperazine-2,5-dione (methyl 2,5-dioxopiperazine-l-dithiocarboxylate) and l,4-bis[methylthio(thiocarbonyl)]piperazine-2,5-dione (107), but when the reaction was carried out in dimethyl sulfoxide containing tetrahydrofuran it afforded (107) plus 3-[bis(methylthio)methylene]-l-methylthio(thiocarbonyl)piperazine-2,5-dione (108) (1630). 

Dinitro-3,6-dimethyl-2,5-diketopiperazine or 1,4-Dinitro-3,6-dimethyl-2,5-dioxopiperazine,... 

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