Perhydro-1,4-dioxopyrrolo pyrazines

The different molecular shapes of diastereoisomeric diketopiperazines allows their ready separation on GLC columns. Whereas with most monocyclic diketopiperazines the dl compounds have shorter retention times than the ll isomers, the reverse is true for perhydro-1,4-dioxopyrrolo[l,2-a]pyrazines. The high degree of diastereoisomeric resolution of these compounds has been studied on a variety of columns. As diastereoisomeric diketopiperazines are more readily separated and studied as their iV-methyl derivatives, GLC and PMR data have been collected for cyclo-L-prolylsarcosine. ... 

Workers at Sandoz have prepared a series of perhydro-1,4-dioxopyrrolo[l,2-a]pyrazines in high yield using the methyl esters of iV-prolylamino acids. " " These esters (128) were obtained by hyd-rogenolysis of the N-benzyloxycarbonyl derivatives (127) over palladium in either acetic acid alone or admixed with ethylacetate. The cyclized products are formed by heating the filtered reaction mixture or by evaporation of the solution followed by heating the residue in vacuo. 

Alkylation of perhydro-l,4-dioxopyrrolo[l,2-a]pyrazines with triethyl-oxonium fluoroborate gives l-ethoxy-4-oxo compounds such as 129. These have then been allowed to react with anthranilic acid to give fused quinazolines such as 130. ... 

Acyl derivatives of perhydro-l,4-dioxopyrrolo[l,2-a]pyrazines are rapidly hydrolyzed to the 2-unsubstituted compounds under very mild conditions. The 2-pyruvoyl compound 86 loses the N-acyl group on boiling in water or methanol, on treatment with ammonia in methylene chloride, on exposure to dilute sodium hydroxide solution, and on treatment with p-toluidine at 50-60° for 30 sec. Similarly the methoxy-propionyl compound 142 is extremely sensitive to alkali, immediately reacting with 0.1 M sodium hydroxide solution at 0°. This compound is also deacylated by ammonium hydroxide solution in a few minutes or by sodium bicarbonate solution after several hours. This behavior contrasts sharply with that of the isomeric oxazolo compound 143 and helps to justify the tricyclic formulation adopted for such compounds. Hydrolysis of the 3S,8aS isomer of compound 142 is accompanied by rapid inversion... 

Reduction of perhydro-l,4-dioxopyrrolo[l,2-a]pyrazines with lithium aluminum hydride gives the expected completely reduced ring system. Recently it has been shown that catalytic hydrogenation of the ben-zylidene compound 144 over palladium proceeds with high asymmetric induction to give the L-prolyl diketopiperazine of an L-amino acid/"" This reaction, followed by acid hydrolysis of the product, provides a new synthesis of optically active amino acids such as L-dopa or l-phenylalanine. 

The ubiquitous nature of proline-containing peptides results in the common appearance of perhydro-l,4-dioxopyrrolo[l,2-a]pyrazines as a result of metabolic processes, particularly of microorganisms. For example, the diketopiperazines 152 were found to be metabolic products of the algae species Scenedesmus sp. These compounds have also been found in cultures of Sfreptomyces. " Glycyl-L-prolyl diketopiperazine has recently been isolated from the small sea animal Luidia clathrata The anhydrides 152 were not directly formed from the constituent amino... 

Much of the interest in perhydro-l,4-dioxopyrrolo[l,2-a]pyrazines has centered around their use in the syntheses of peptide-containing ergot alkaloids and their Typical is the... 

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