2.5- Dioxopiperazines

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. 

The alkaline fission may be represented similarly. (8-Addition of hydroxide ion to the benzylidene double bond would lead to 130 which by a rather surprising elimination of the A-hydroxyl group could give the acyl dioxopiperazine (128). Cleavage of 128 by ammonia to give a benzamide is unexceptional. Birch et al. noted in 1966 that no... 

Treatment of the indole derivative 290 with trifluoroacetic acid gave the addition product 291 that upon cyclization afforded the pyridoindole derivative 292 (81H713). Treatment of 290 which has a dioxopiperazine ring on C-3 with boron trifluoride etherate gave a mixture of pyrroloindole 293... 

Chemical Name dl-1,2-Bis(3,5-dioxopiperazin-1-yl)propane Common Name —... 

The intriguing formation of a few dioxopiperazines 12 opens new problems of competitive regiochemistry and stereochemistry. Related synthetic, x-ray, and theoretical studies are currently carried out (Ref. 18). 

Treatment of the multifunctionalized dioxopiperazine 437 with acid results in cyclization with loss of methanol (Equation 179) <2004T6319>. 

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. 

Dioxopiperazine formation is avoided by esterifying the carboxy terminus of a chain with a tertiary alcohol, which provides a poor leaving group, tert-Butyl and... 

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. 

A recent review of the metabolites of L. maculans and L biglobosa produced in diverse culture conditions [19] emphasized that both species biosynthesize host-selective and non-selective phytotoxins. Importantly, it was shown that the composition of metabolite profiles of L. maculans depended on the composition of the culture medium. In a chemically defined liquid medium, isolates virulent on canola produced mainly sirodesmin PL (1), a non-host-selective phytotoxin, minor sirodesmins with one, three, or four sulfurs bridging the dioxopiperazine ring (sirodesmin H (3) [20], sirodesmin J (4) and K (5) [21]) and phomalirazine (6) (Fig. 9.1). The various sirodesmins 1-5 and phomalirazine (6) caused necrotic lesions of different intensities on leaves of both resistant and susceptible plants. Phomalide (7), the first host-selective phytotoxin isolated from virulent isolates of L. maculans, caused disease symptoms (necrotic, chlorotic, and reddish lesions) on canola (susceptible to L maculans) but not on brown mustard or white mustard... 

Several bis(dioxopiperazines) exhibit antitumor activity. Thus, ICRF 159 122 is an inhibitor of DNA synthesis, blocks the cell cycle in G2-M phase and inhibits metastases in the Lewis lung tumor (3LL) animal model without impeding the... 

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. 

The chiral, nonracemic, tricyclic dioxopiperazine derivative 1, easily obtained from proline, is transformed with sodium amide in liquid ammonia into its monoenolate, then alkylated with bromoethane to give the chiral, nonracemic ethylation product 2. On deprotonation and further alkylation. 2 furnishes the achiral fra/w-dialkylated product 3 in good yield1. 

The starting dioxopiperazine (L-prolinyl-L-proline anhydride, 1) is prepared from the ethyl ester of i.-pro-line by storage over concentrated sulfuric acid in a desiccator for 3 weeks yield 59% [a]D — 137.2 (c = 3.5, CHC1,). 

The regio- and stereoselective alkylations of a number of bicyclic racemic dioxopiperazines have been reported3. For example, dioxopiperazine 9 is deprotonated by lithium diisopropyl-amide in tetrahydrofuran at — 78 °C to yield a monoanion. Alkylation with iodomethane in the presence of hexamethylphosphoric triamide gives products 10 and 11 in a 81 19 ratio and 75 % yield based on recovered starting material3. 

Diketopiperazine 3,5-Dioxopiperazine Glycine Anhydride Cycloglycylglycin or Lactam of Glycylglycin... 

Aliphatic amino acids are converted into (trifluoromethyl)amines 12 by treatment with sulfur tetrafluoride in hydrogen fluoride. Hydrogen fluoride simultaneously protects the amino group by protonation and serves as a catalyst.113 The reactions proceed with retention of configuration. Yields of (trifluoromethyl)amines from a-amino acids vary from very low to approximately 40% and are limited by the formation of dioxopiperazines.113... 

Secondary a-amino acids in which formation of dioxopiperazines is hindered, c.g. A-dodec-ylalanine (13), give better yields of the corresponding (trifluoromethyl)amines.113... 

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

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