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Acta Crystallogr Sect E Struct Rep Online. 2010 February 1; 66(Pt 2): o417–o418.
Published online 2010 January 23. doi:  10.1107/S1600536810001856
PMCID: PMC2979809

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

Abstract

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].

Related literature

For general background to the chemistry and biological properties of diketopiperazines, see: Herbert & Kelleher (1994 [triangle]); Ciajolo et al. (1995 [triangle]); Morley et al. (1981 [triangle]); Kazuharu et al. (1990 [triangle]); Funabashi et al. (1994 [triangle]); Moyroud et al. (1996 [triangle]); Caballero et al. (2003 [triangle]); Onishi et al. (2003 [triangle]); Alberch et al. (2004 [triangle]); von Nussbaum et al. (2003 [triangle]). For related structures, see: Hendea et al. (2006 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-66-0o417-scheme1.jpg

Experimental

Crystal data

  • C9H14N2O2
  • M r = 182.22
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-66-0o417-efi2.jpg
  • a = 6.8657 (4) Å
  • b = 9.9258 (17) Å
  • c = 7.0040 (5) Å
  • β = 90.892 (6)°
  • V = 477.25 (9) Å3
  • Z = 2
  • Mo Kα radiation
  • μ = 0.09 mm−1
  • T = 293 K
  • 0.46 × 0.40 × 0.33 mm

Data collection

  • Enraf–Nonius CAD-4 diffractometer
  • 1290 measured reflections
  • 1200 independent reflections
  • 937 reflections with I > 2σ(I)
  • R int = 0.032
  • 3 standard reflections every 200 reflections intensity decay: 1%

Refinement

  • R[F 2 > 2σ(F 2)] = 0.044
  • wR(F 2) = 0.120
  • S = 1.09
  • 1200 reflections
  • 119 parameters
  • 1 restraint
  • H-atom parameters constrained
  • Δρmax = 0.17 e Å−3
  • Δρmin = −0.15 e Å−3

Data collection: CAD-4 Software (Enraf–Nonius, 1989 [triangle]); cell refinement: CAD-4 Software; data reduction: HELENA (Spek, 1996 [triangle]); program(s) used to solve structure: SIR97 (Altomare et al., 1999 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: PLATON (Spek, 2009 [triangle]) and Mercury (Macrae et al., 2006 [triangle]); software used to prepare material for publication: SHELXL97.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536810001856/bh2268sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810001856/bh2268Isup2.hkl

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Acknowledgments

The authors are grateful to the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), the Fundação de Apoio à Pesquisa Científica e Tecnológica do Estado de Santa Catarina (FAPESC) and the Instituto Nacional de Ciência e Tecnologia (INCT)–Catálise for financial assistance.

supplementary crystallographic information

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 1H-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···O4i [symmetry code: (i) -x + 2, y + 1/2, -z] interactions promote the formation of parallel one-dimensional zigzag C(5) chains running on the 21 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) was added Pd/C (10%, 18 mg, three portions of 6 mg of the catalyst were added each 10 h) and the mixture was shaken under 40 psi of hydrogen at room temperature for 28 h and 30 min [TLC control, alumina, ethyl acetate/hexane (1:3 v/v)]. After filtration of the catalyst, the solvent was evaporated under reduced pressure and column chromatography of the residue over alumina with ethyl acetate afforded compound (I) as a white solid, with 84% yield. A careful crystallization from ethyl acetate/hexane (1:3 v/v) provided crystals (mp. 133.5–134.5°C) suitable for X-ray analysis.

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, CH2 and CH3, respectively. Uiso of the H atoms were fixed at 1.2 times for methine and methylene and 1.5 times for methyl of the Ueq 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 Uiso was also fixed at 1.2 times Ueq of the parent N atom.

Figures

Fig. 1.
Synthetic route.
Fig. 2.
The molecular structure of the title compound with labeling scheme. Displacement ellipsoids are shown at the 40% probability level.
Fig. 3.
Polymeric chain along b axis formed by intermolecular hydrogen bonding. Symmetry code: -x + 2, y + 1/2, -z
Fig. 4.
Partial packing of the title compound showing the stacking of the molecules along [100] (top) and along [010] (bottom).

Crystal data

C9H14N2O2F(000) = 196
Mr = 182.22Dx = 1.268 Mg m3
Monoclinic, P21Melting point: 407 K
Hall symbol: P 2ybMo Kα radiation, λ = 0.71073 Å
a = 6.8657 (4) ÅCell parameters from 25 reflections
b = 9.9258 (17) Åθ = 3.6–15.6°
c = 7.0040 (5) ŵ = 0.09 mm1
β = 90.892 (6)°T = 293 K
V = 477.25 (9) Å3Prism, colorless
Z = 20.46 × 0.40 × 0.33 mm

Data collection

Enraf–Nonius CAD-4 diffractometerRint = 0.032
Radiation source: fine-focus sealed tubeθmax = 27.9°, θmin = 3.0°
graphiteh = −9→9
ω–2θ scansk = −13→0
1290 measured reflectionsl = −9→0
1200 independent reflections3 standard reflections every 200 reflections
937 reflections with I > 2σ(I) intensity decay: 1%

Refinement

Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.044Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.120H-atom parameters constrained
S = 1.09w = 1/[σ2(Fo2) + (0.0525P)2 + 0.0801P] where P = (Fo2 + 2Fc2)/3
1200 reflections(Δ/σ)max < 0.001
119 parametersΔρmax = 0.17 e Å3
1 restraintΔρmin = −0.15 e Å3
0 constraints

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)

xyzUiso*/Ueq
C10.6671 (5)0.5429 (3)0.1100 (4)0.0446 (7)
C30.8672 (4)0.3662 (3)−0.0490 (4)0.0446 (7)
H31.00830.3519−0.04000.054*
C40.7726 (4)0.2617 (3)0.0781 (4)0.0428 (7)
C60.5113 (5)0.2151 (3)0.3021 (5)0.0481 (7)
H6A0.59120.19660.41450.058*
H6B0.47320.13040.24350.058*
C70.3339 (5)0.2985 (4)0.3527 (5)0.0646 (10)
H7A0.30150.28670.48600.077*
H7B0.22230.27320.27410.077*
C80.3944 (5)0.4437 (4)0.3131 (5)0.0603 (9)
H8A0.28160.50010.28780.072*
H8B0.46810.48100.41990.072*
C8A0.5200 (4)0.4315 (3)0.1373 (4)0.0415 (6)
H8AA0.43530.42630.02370.050*
C90.8066 (5)0.3439 (4)−0.2576 (5)0.0572 (9)
H9A0.83510.2514−0.29240.069*
H9B0.66700.3568−0.27050.069*
C100.9082 (6)0.4374 (5)−0.3946 (5)0.0691 (11)
H10A1.04660.4307−0.37530.104*
H10B0.86730.5284−0.37200.104*
H10C0.87510.4124−0.52350.104*
N20.8290 (4)0.5027 (2)0.0198 (4)0.0486 (7)
H20.91290.5629−0.01710.058*
N50.6154 (3)0.3007 (2)0.1667 (3)0.0396 (6)
O10.6391 (4)0.6573 (2)0.1630 (4)0.0643 (7)
O40.8399 (4)0.1481 (2)0.0937 (4)0.0655 (7)

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
C10.0549 (17)0.0338 (15)0.0452 (15)0.0027 (13)−0.0003 (13)0.0037 (13)
C30.0380 (15)0.0432 (17)0.0528 (16)0.0016 (12)0.0064 (13)0.0008 (14)
C40.0405 (15)0.0384 (15)0.0494 (16)0.0032 (13)0.0012 (13)−0.0032 (13)
C60.0556 (18)0.0402 (16)0.0486 (16)−0.0063 (14)0.0040 (14)0.0026 (14)
C70.061 (2)0.067 (2)0.066 (2)0.0009 (19)0.0250 (16)0.005 (2)
C80.065 (2)0.050 (2)0.067 (2)0.0113 (17)0.0253 (16)0.0011 (17)
C8A0.0415 (14)0.0351 (14)0.0480 (15)0.0053 (13)0.0043 (12)0.0018 (12)
C90.066 (2)0.055 (2)0.0507 (17)−0.0062 (16)0.0063 (16)−0.0058 (15)
C100.077 (2)0.079 (3)0.0526 (19)−0.003 (2)0.0156 (17)−0.0057 (19)
N20.0534 (15)0.0378 (14)0.0549 (15)−0.0127 (12)0.0085 (12)−0.0031 (11)
N50.0416 (13)0.0317 (12)0.0457 (13)0.0024 (10)0.0051 (10)0.0018 (11)
O10.0847 (18)0.0346 (12)0.0737 (16)0.0033 (12)0.0073 (14)−0.0050 (12)
O40.0627 (14)0.0468 (14)0.0875 (17)0.0208 (12)0.0180 (12)0.0095 (13)

Geometric parameters (Å, °)

C1—O11.210 (4)C7—H7A0.9700
C1—N21.347 (4)C7—H7B0.9700
C1—C8A1.512 (4)C8—C8A1.519 (4)
C3—N21.464 (4)C8—H8A0.9700
C3—C41.519 (4)C8—H8B0.9700
C3—C91.529 (4)C8A—N51.468 (4)
C3—H30.9800C8A—H8AA0.9800
C4—O41.223 (4)C9—C101.513 (5)
C4—N51.312 (4)C9—H9A0.9700
C6—N51.467 (4)C9—H9B0.9700
C6—C71.519 (5)C10—H10A0.9600
C6—H6A0.9700C10—H10B0.9600
C6—H6B0.9700C10—H10C0.9600
C7—C81.527 (6)N2—H20.8717
O1—C1—N2123.9 (3)C8A—C8—H8B111.1
O1—C1—C8A122.5 (3)C7—C8—H8B111.1
N2—C1—C8A113.6 (3)H8A—C8—H8B109.0
N2—C3—C4111.0 (2)N5—C8A—C1111.6 (2)
N2—C3—C9113.7 (3)N5—C8A—C8102.4 (2)
C4—C3—C9110.4 (3)C1—C8A—C8115.7 (3)
N2—C3—H3107.1N5—C8A—H8AA109.0
C4—C3—H3107.1C1—C8A—H8AA109.0
C9—C3—H3107.1C8—C8A—H8AA109.0
O4—C4—N5122.8 (3)C10—C9—C3113.3 (3)
O4—C4—C3121.2 (3)C10—C9—H9A108.9
N5—C4—C3116.0 (3)C3—C9—H9A108.9
N5—C6—C7103.6 (3)C10—C9—H9B108.9
N5—C6—H6A111.0C3—C9—H9B108.9
C7—C6—H6A111.0H9A—C9—H9B107.7
N5—C6—H6B111.0C9—C10—H10A109.5
C7—C6—H6B111.0C9—C10—H10B109.5
H6A—C6—H6B109.0H10A—C10—H10B109.5
C6—C7—C8104.5 (3)C9—C10—H10C109.5
C6—C7—H7A110.8H10A—C10—H10C109.5
C8—C7—H7A110.8H10B—C10—H10C109.5
C6—C7—H7B110.8C1—N2—C3125.6 (3)
C8—C7—H7B110.8C1—N2—H2119.3
H7A—C7—H7B108.9C3—N2—H2114.5
C8A—C8—C7103.4 (3)C4—N5—C6123.2 (3)
C8A—C8—H8A111.1C4—N5—C8A124.3 (2)
C7—C8—H8A111.1C6—N5—C8A112.5 (2)
N2—C3—C4—O4−152.4 (3)O1—C1—N2—C3−179.1 (3)
C9—C3—C4—O480.6 (4)C8A—C1—N2—C30.2 (4)
N2—C3—C4—N528.2 (4)C4—C3—N2—C1−31.8 (4)
C9—C3—C4—N5−98.8 (3)C9—C3—N2—C193.3 (3)
N5—C6—C7—C8−23.9 (4)O4—C4—N5—C63.8 (5)
C6—C7—C8—C8A36.4 (4)C3—C4—N5—C6−176.8 (3)
O1—C1—C8A—N5−147.5 (3)O4—C4—N5—C8A−173.9 (3)
N2—C1—C8A—N533.2 (3)C3—C4—N5—C8A5.4 (4)
O1—C1—C8A—C8−31.1 (4)C7—C6—N5—C4−175.5 (3)
N2—C1—C8A—C8149.7 (3)C7—C6—N5—C8A2.5 (3)
C7—C8—C8A—N5−33.9 (3)C1—C8A—N5—C4−37.8 (4)
C7—C8—C8A—C1−155.4 (3)C8—C8A—N5—C4−162.1 (3)
N2—C3—C9—C1059.2 (4)C1—C8A—N5—C6144.3 (3)
C4—C3—C9—C10−175.3 (3)C8—C8A—N5—C620.0 (3)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N2—H2···O4i0.871.982.817 (3)161

Symmetry codes: (i) −x+2, y+1/2, −z.

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: BH2268).

References

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