Diketopiperazines stereochemistry

Wyatt PG, Allen MJ, Borthwick AD, Davies DE, Exall AM, Hatley RJD, Irving WR, Livermore DG, Miller ND, Nerozzi F et al (2005) 2, 5-diketopiperazines as potent and selective oxytocin antagonists-1 identification, stereochemistry and initial SAR. Bioorg Med Chem Lett 15 2579-2582... 

Roquefortine.—Histidine (121) is a part precursor for roquefortine (119) (cf. Vol. 10, p. 25). Its incorporation involves desaturation with loss of the proton at C-2 and one of the protons at C-3. Experimental results with (2S,3S)- and (25,3jR)-[3-3H]histidine [as (121)] show that, in the biosynthesis of both roquefortine (119) and oxaline (120), the 3-pro-S proton is lost stereo-specifically.43 Dehydrogenation to generate these double-bonds of (E) configuration thus proceeds in a syn sense. Desaturation with the same syn stereochemistry has been observed in the biosynthesis of other diketopiperazine metabolites, e.g. mycelianamide and cryptoechinulin A, which both have (Z) double-bonds (cf. Vol. 7, p. 19 Vol. 8, p. 35). 

These bromides are useful for the synthesis of asymmetric diketopiperazines. In order to obtain bromoglycine derivatives for use in stereocontrolled synthesis, chiral auxiliaries have been attached to the amino and carboxy groups of glycine before bromination. For example, the bromides 1-4 have been prepared in this manner [16-19]. They were obtained as various mixtures of diastereomers, but this stereochemistry is not particularly important as their reactions mostly involve intermediates that are planar at the a-carbon. 

Aranotin 47, a diketopiperazine containing the oxepine nucleus, is a metabolite from Arachniotus aureus and showed antiviral activity. The structure and the stereochemistry of 47 appear to represent a biogenetic transformation of a benzene ring into the oxepine nucleus. 

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