(3R,8aS)-3-Ethylperhydropyrrolo[1,2-a]pyrazine-1,4-dione

In the title compound, C9H14N2O2, the pyrrolidine and piperazine rings adopt envelope and boat conformations, respectively. The chiral centers were assigned on the basis of the known stereogenic center of an enantiomerically pure starting material and the trans relationship between the H atoms attached to these centers. The crystal packing is stabilized by an intermolecular hydrogen bond between the N—H group and a carbonyl O atom of the diketopiperazine group, forming zigzag C(5) chains along [010].

In the title compound, C 9 H 14 N 2 O 2 , the pyrrolidine and piperazine rings adopt envelope and boat conformations, respectively. The chiral centers were assigned on the basis of the known stereogenic center of an enantiomerically pure starting material and the trans relationship between the H atoms attached to these centers. The crystal packing is stabilized by an intermolecular hydrogen bond between the N-H group and a carbonyl O atom of the diketopiperazine group, forming zigzag C(5) chains along [010].
Moyroud, J., Gelin, J., Chê ne, A. & Mortier, J. (1996). Tetrahedron, 52, 8525-8534. Nussbaum, F. von (2003 Comment Diketopiperazine (DKP) backbone is an important pharmacophore in medicinal chemistry, which is conformationally restrained by six-membered ring with side chains that are oriented in a spatially defined manner (Herbert & Kelleher, 1994;Ciajolo et al., 1995). DKPs are quite common in nature and many natural products with the DKP scaffold have been isolated encompassing a wide range of biological activities (Morley et al., 1981;Kazuharu et al., 1990;Funabashi et al., 1994;Moyroud et al., 1996). Several secondary metabolites of microorganisms with interesting biological properties contain a proline-derived diketopiperazine as part of their molecular skeleton (Caballero et al., 2003;Onishi et al., 2003;Alberch et al., 2004;von Nussbaum et al., 2003). During our work on the synthesis of L-proline-based DKPs, we prepared L-proline methyl ester derivative (II) which, under hydrogenolysis condition, led to the title compound (I, Fig. 1). Despite its full chemical characterization and the known configuration of the starting material L-proline, the absolute configuration at C3 was tentatively assigned as being R due to the trans relationship of the hydrogen atoms attached to carbons C3 and C8a based on 1 H-NMR and NOE experiments. The crystallographic data unambiguously confirmed the trans relationship of the above mentioned hydrogen atoms and consequently the R configuration of the chiral center at C3 (Fig. 2).
The molecular structure of (I) consists of a bicycle system formed by pyrrolidine and piperazine fused rings (Hendea et al., 2006). The five-membered pyrrolidine ring shows an envelope conformation, which is enveloped at C8. Piperazine ring shows perfect boat conformation, where N2, C1, C4 and N5 atoms lie on the basal plane (r.m.s. deviation: 0.0016 Å) and C3 and C8a are out of the basal mean plane by 0.39 Å (average) toward the same direction.
Strong intermolecular hydrogen bonds between the N-H group and the carbonyl O atom of the diketopiperazine neighboring groups contribute to the stabilization of the crystal structure. N2-H2···O4 i [symmetry code: (i) -x + 2, y + 1/2, -z] interactions promote the formation of parallel one-dimensional zigzag C(5) chains running on the 2 1 screw axis along [010] (Fig. 3). Furthermore, the molecules of (I) are stacked viewing in perpendicular projection of the chains, along [100], and viewing in parallel projection of the chains, along [010] (Fig. 4).

Experimental
To a solution of L-proline methyl ester derivative (II) (0.084 mmol) in methanol (6 ml supplementary materials sup-2 Refinement All non-H atoms were refined with anisotropic displacement parameters. H atoms were placed at their idealized positions with distances of 0.98, 0.97 and 0.96 Å for CH, CH 2 and CH 3 , respectively. U iso of the H atoms were fixed at 1.2 times for methine and methylene and 1.5 times for methyl of the U eq of the carrier C atom. Hydrogen atom of the cyclic piperazine amine group was found in a difference map and treated with a riding model and its U iso was also fixed at 1.2 times U eq of the parent N atom.