Hydroxy-piperazinediones

V. Synthesis of ot-Hydroxy- and a-Mercapto-a-amino Acids, a,a-Diamino Acids and the Corresponding Peptides and Piperazinediones.282... 

The available data on piperazinediones have been the subject of a recent detailed survey by P. G. Sammes (341). Since then only few additional reports on naturally occurring unsaturated cyclodipeptides (91, 188, 189, 204, 248, 249), 3-hydroxy substituted cyclodipeptides (2) (124, 440) and epidithiocyclopeptides (27, 36, 135, 260, 399) have been published. 

O, D) A hypothetical pathway is the formation of an acylimino acid unit by N-hydroxylation of the amino acid within the peptide chain followed by loss of water. a-Acylimino carboxylic acid derivatives readily rearrange to acylenamino carboxylic acid derivatives 314). N-Hydroxy compounds, such as mycelianamide and pulcherrimic acid [for a review on cyclic hydroxamic acids see ref. (26)], have been found within the class of dehydrocyclopeptides. Although N-hydroxypyra-zinones are common, it is not known whether these compounds are biogenetically linked with the piperazinediones. It is appropriate to point out that N-hydroxylation of amides is a familiar degradative pathway in the metabolic processes of higher organisms 412). The facile elimination of water from N-acylhydroxylamino acids to form acylenamino acids 377) should also be noted in this context. 

K) A final route which cannot a priori be excluded as a possible biosynthetic pathway is the direct a-oxidation of amino acid derivatives to a-hydroxy-a-amino acid derivatives followed by elimination of water. In vitro oxidation of piperazinediones to a-hydroperoxides occurs very readily (cf. Section V.). The isolation of numerous dehydropiperazine-diones and corresponding mercaptopiperazinediones containing proline (or benzoproline , i. e. dihydroindole) units 341) necessitates the consideration of this route as a possible biosynthetic pathway. The hydroperoxypiperazinediones can readily be converted into dehydro-and mercaptopiperazinediones. 

Direct nucleophilic substitution reactions between e. g. thiolacetate or thiolate and halogenated piperazinediones or piperazinediones with hydroxy-, acetoxy- or sulfone substituents 283, 284, 307, 416). 

In the following, detailed treatment will be restricted to more modem approaches to piperazinediones with sulfur substituents based on the formation and transformation of the corresponding hydroxy compounds. 

---