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ISSN: 2056-9890

(1S,2R,6R,7aS)-1,2,6-Trihy­dr­oxy­hexa­hydro-1H-pyrrolizin-3-one

aLaboratory of Structural Biology and Crystallography, Institute of Chemistry, University of Campinas, CP6154, CEP 13083-970, Campinas-SP, Brazil, and bLaboratory of Synthesis of Natural Products and Drugs, Institute of Chemistry, University of Campinas, CP6154, CEP 13083-970, Campinas-SP, Brazil
*Correspondence e-mail: aparicio@iqm.unicamp.br

(Received 13 December 2011; accepted 18 January 2012; online 4 February 2012)

In the title compound, C7H11NO4, prepared via a Morita–Baylis–Hillman adduct, the five-membered ring bearing three O atoms approximates to a twisted conformation, whereas the other ring is close to an envelope, with a C atom in the flap position. The dihedral angle between their mean planes (all atoms) is 23.11 (9)°. The new stereocenters are created in a trans-diaxial configuration. In the crystal, O—H⋯O and O—H⋯(O,O) hydrogen bonds link the mol­ecules, generating a three-dimensional network. A weak C—H⋯O inter­action also occurs.

Related literature

For the utilization of this type of pyrrolizidinone as an inihibitor of glicosidase, see: D'Alanzo et al. (2009)[D'Alanzo, D., Guaragna, A. & Palumbo, G. (2009). Curr. Med. Chem. 16, 473-505.]; Ayad et al. (2004[Ayad, T., Génisson, A. & Baltas, M. (2004). Curr. Med. Chem. 8, 1211-1233.]) and for their huge therapeutical potential for the treatment of a number of diseases such as cancer, diabetes, and lysosomal storage disorders, see: Baumann (2007[Baumann, K. (2007). WO Patent 2007039286; Chem. Abstr. 146, 421836.]). For related literature concerning preparation of the title compound, see: Freire et al. (2007[Freire, K. R. L., Tormena, C. F. & Coelho, F. (2011). Synlett, pp. 2059-2063.]). Analysis of the absolute structure was also performed using likelihood methods, see: Hooft et al. (2008[Hooft, R. W. W., Straver, L. H. & Spek, A. L. (2008). J. Appl. Cryst. 41, 96-103.]).

[Scheme 1]

Experimental

Crystal data
  • C7H11NO4

  • Mr = 173.17

  • Monoclinic, P 21

  • a = 4.6983 (3) Å

  • b = 14.5424 (10) Å

  • c = 5.5271 (4) Å

  • β = 99.663 (3)°

  • V = 372.28 (4) Å3

  • Z = 2

  • Cu Kα radiation

  • μ = 1.09 mm−1

  • T = 100 K

  • 0.31 × 0.27 × 0.25 mm

Data collection
  • Bruker Kappa APEXII DUO diffractometer

  • 3697 measured reflections

  • 1229 independent reflections

  • 1228 reflections with I > 2σ(I)

  • Rint = 0.027

Refinement
  • R[F2 > 2σ(F2)] = 0.029

  • wR(F2) = 0.073

  • S = 1.14

  • 1229 reflections

  • 112 parameters

  • 1 restraint

  • H-atom parameters constrained

  • Δρmax = 0.27 e Å−3

  • Δρmin = −0.41 e Å−3

  • Absolute structure: Flack (1983[Flack, H. D. (1983). Acta Cryst. A39, 876-881.]), 537 Friedel pairs

  • Flack parameter: 0.20 (17)

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
O1—H1⋯O2i 0.84 1.98 2.8190 (15) 174
O2—H2⋯O1ii 0.84 2.50 3.1745 (15) 138
O2—H2⋯O4iii 0.84 2.25 2.8589 (15) 129
O4—H4⋯O3iv 0.84 1.84 2.6636 (15) 167
C4—H4A⋯O4ii 1.00 2.41 3.3057 (18) 148
Symmetry codes: (i) [-x+1, y-{\script{1\over 2}}, -z+2]; (ii) [-x+1, y+{\script{1\over 2}}, -z+1]; (iii) [-x, y+{\script{1\over 2}}, -z+1]; (iv) x-1, y, z-1.

Data collection: APEX2 (Bruker, 2010)[Bruker (2010). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]; cell refinement: SAINT (Bruker, 2010[Bruker (2010). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: WinGX (Farrugia,1999[Farrugia, L. J. (1999). J. Appl. Cryst. 32, 837-838.]) and PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]); software used to prepare material for publication: publCIF (Westrip, 2010[Westrip, S. P. (2010). J. Appl. Cryst. 43, 920-925.]) and PLATON.

Supporting information


Comment top

Crystallographic data of the title polyhydroxylated pyrrolizidinone are disclosed. Compounds of this class can be used as glycosidase inhibitors and present a huge therapeutical potential for the treatment of a number of diseases such as cancer, diabetes, and lysosomal storage disorders (Baumann, 2007). The title compound has been prepared, for the first time, using a synthetic strategy based on a Morita-Baylis-Hillman adduct, easily obtained from a reaction between N-Boc-4(R)-hydroxy-2(S)-prolinal and methyl acrylate in 70% yield, as a mixture of diastereoisomers. After chromatographic separation, the minor isomer was transformed into the title compound. This compound was synthesized in five steps and 5.2% overall yield.

The asymmetric pyrrolizidinone, C7H11NO4, a new molecule with four stereocenters from a Morita-Baylis-Hillman adduct is shown in Fig. 1. The crystal packing (Fig. 2) is stabilized by hydrogen bonds. The dihedral angles of H7—C7—C6—H6 = 153.8° and H1A—C1—C7—H7 = 161.6° show that the H atoms 1A, 7 and 6 of the two new stereocenters are created in the trans-diaxial configuration. These values agree with the coupling constants values obtained for these protons in the 1H NMR analysis, 3JH6,H7 = 7.2 Hz e 3JH1A,H7 = 8.8 Hz. The crystallography parameters for this new molecule confirm its absolute configuration.

Related literature top

For the utilization of this type of pyrrolizidinone as an inihibitor of glicosidase, see: D'Alanzo et al. (2009); Ayad et al. (2004) and for their huge therapeutical potential for the treatment of a number of diseases such as cancer, diabetes, and lysosomal storage disorders, see: Baumann (2007). For related lieterature [on what subject?], see: Freire & Coelho (2007). Analysis of the absolute structure was also performed using likelihood methods, see: Hooft et al. (2008).

Experimental top

A solution of pyrrolizidinone (II) (0.10 g, 0.59 mmol) in MeOH/CH2Cl2 (3:7, 15 mL) was cooled to -72°C. After that a stream of oxygen/ozone was bubbled into it for 8–10 min (the reaction evolution was followed by TLC). Then, NaBH4 (0.112 g, 4.45 mmol) was added at -72°C and the resulting mixture was stirred for 6 h at room temperature. The reaction medium was initially acidified to pH 2–3 with a solution of HCl in methanol, then it was neutralized to pH 6–7 with solid Na2CO3. The resulting mixture was filtered over a pad of Celite(R) and the solid was washed with methanol. The filtrates were combined and the solvents were removed under reduced pressure. The residue was purified by flash silica gel column chromatography (CH2Cl2:MeOH 95:05) to afford pyrrolizidinone I (0.08 g), as a white solid, in 80% yield. The title compound was recrystallized by using the liquid-vapor saturation method. The compound was dissolved with ethanol and crystallized with a vapor pressure of a second less polar liquid (chloroform), in a closed camera, providing the slow formation of crystals. [α]D20 + 3 (c 1, MeOH); M. p. 150–152°C; IR (KBr, vmax): 3499, 3374, 2993, 2910, 1681, 1446, 1362, 1327, 1262, 1129, 1111, 1014 cm-1; 1H NMR (400 MHz, D2O) δ 1.78 (ddd, J 13.4, 5.0, 4.9 Hz, 1H, H-5B); 2.28 (dd, J 13.4, 5.7 Hz, 1H, H-5 A); 3.10 (d, J 12.8 Hz, 1H, H-3B; 3.77 (dd, J 12.9, 4.9 Hz, 1H, H-3 A); 3.91 (m, 1H, H-6); 3.99 (dd, JH7,H1A 8.8, JH6,H7 7.2 Hz, 1H, H-7); 4.60 (d, JH7,H1A 8.8 Hz, 1H, H-1 A); 4.70 (t, J 4.9 Hz, 1H, H-4 A); 13C NMR (62.5 MHz, MeOD) δ 40.7, 52.1, 63.0, 73.2, 80.1, 83.3, 174.0; HRMS (ESI-TOF) Calcd. for C7H12NO4 [M + H]+ 174.0766, Found 174.0754.

Refinement top

The calculated Flack parameter was F=0.20 (17) (Flack, 1983). Analysis of the absolute structure was also performed using likelihood methods (Hooft et al., 2008) as implemented in PLATON (Spek, 2009). The resulting value for the Hooft parameter was y=0.12 (4), with a corresponding probability for an inverted structure smaller than 1 × 10-100. Taken togheter, these results indicate that the absolute structure has been determined correctly.

Computing details top

Data collection: APEX2 (Bruker, 2010); cell refinement: SAINT (Bruker, 2010); data reduction: SAINT (Bruker, 2010); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: WinGX (Farrugia,1999) and PLATON (Spek, 2009); software used to prepare material for publication: publCIF (Westrip, 2010) and PLATON (Spek, 2009).

Figures top
[Figure 1] Fig. 1. Molecular view of the title compound showing displacement ellipsoids drawn at the 50% probability level. H atoms are presented as a small spheres of arbitrary radius.
[Figure 2] Fig. 2. Title compound involved into hydrogen bonds. The presence of several hydroxyl groups in its structure leads this compound to behave as a sugar.
[Figure 3] Fig. 3. The conversion of (I) to pyrrolizidinone (II).
(1S,2R,6R,7aS)-1,2,6-Trihydroxyhexahydro- 1H-pyrrolizin-3-one top
Crystal data top
C7H11NO4F(000) = 184
Mr = 173.17Dx = 1.545 Mg m3
Monoclinic, P21Cu Kα radiation, λ = 1.54178 Å
a = 4.6983 (3) ÅCell parameters from 1229 reflections
b = 14.5424 (10) Åθ = 6.1–66.8°
c = 5.5271 (4) ŵ = 1.09 mm1
β = 99.663 (3)°T = 100 K
V = 372.28 (4) Å3Rectangular block, colorless
Z = 20.31 × 0.27 × 0.25 mm
Data collection top
Bruker Kappa APEXII DUO
diffractometer
1228 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tubeRint = 0.027
Graphite monochromatorθmax = 66.8°, θmin = 6.1°
Bruker APEX CCD area–detector scansh = 55
3697 measured reflectionsk = 1616
1229 independent reflectionsl = 66
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.029H-atom parameters constrained
wR(F2) = 0.073 w = 1/[σ2(Fo2) + (0.0498P)2 + 0.0546P]
where P = (Fo2 + 2Fc2)/3
S = 1.14(Δ/σ)max = 0.012
1229 reflectionsΔρmax = 0.27 e Å3
112 parametersΔρmin = 0.41 e Å3
1 restraintAbsolute structure: Flack (1983), 537 Friedel pairs
Primary atom site location: structure-invariant direct methodsAbsolute structure parameter: 0.20 (17)
Crystal data top
C7H11NO4V = 372.28 (4) Å3
Mr = 173.17Z = 2
Monoclinic, P21Cu Kα radiation
a = 4.6983 (3) ŵ = 1.09 mm1
b = 14.5424 (10) ÅT = 100 K
c = 5.5271 (4) Å0.31 × 0.27 × 0.25 mm
β = 99.663 (3)°
Data collection top
Bruker Kappa APEXII DUO
diffractometer
1228 reflections with I > 2σ(I)
3697 measured reflectionsRint = 0.027
1229 independent reflections
Refinement top
R[F2 > 2σ(F2)] = 0.029H-atom parameters constrained
wR(F2) = 0.073Δρmax = 0.27 e Å3
S = 1.14Δρmin = 0.41 e Å3
1229 reflectionsAbsolute structure: Flack (1983), 537 Friedel pairs
112 parametersAbsolute structure parameter: 0.20 (17)
1 restraint
Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
O10.6971 (2)0.03528 (7)0.86162 (19)0.0163 (3)
H10.72220.05941.00160.024*
O20.2633 (2)0.38620 (8)0.6676 (2)0.0167 (3)
H20.18020.41230.53940.025*
O30.9071 (2)0.13035 (8)1.12983 (19)0.0194 (3)
O40.1530 (2)0.02523 (7)0.5015 (2)0.0167 (3)
H40.07150.05040.37140.025*
N10.5577 (3)0.20182 (9)0.8573 (2)0.0128 (3)
C10.5216 (3)0.04341 (11)0.8610 (3)0.0134 (3)
H1A0.35990.03030.95280.016*
C20.6890 (3)0.12859 (11)0.9697 (3)0.0141 (3)
C30.6663 (3)0.29584 (11)0.8577 (3)0.0143 (3)
H3A0.87800.29660.86330.017*
H3B0.61910.33100.99920.017*
C40.5078 (3)0.33520 (10)0.6142 (3)0.0136 (3)
H4A0.63840.37530.53460.016*
C50.4128 (3)0.25050 (10)0.4564 (3)0.0142 (3)
H5A0.24090.26440.33180.017*
H5B0.57010.22860.37210.017*
C60.3420 (3)0.17927 (10)0.6401 (2)0.0124 (3)
H60.14200.18870.67520.015*
C70.3995 (3)0.07635 (12)0.6019 (3)0.0132 (3)
H70.55010.06970.49490.016*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0237 (5)0.0097 (6)0.0144 (5)0.0043 (5)0.0003 (4)0.0025 (5)
O20.0219 (5)0.0113 (6)0.0152 (5)0.0040 (4)0.0017 (4)0.0004 (4)
O30.0229 (6)0.0171 (6)0.0149 (5)0.0001 (5)0.0062 (4)0.0016 (4)
O40.0209 (5)0.0118 (6)0.0141 (5)0.0016 (4)0.0065 (4)0.0014 (4)
N10.0192 (6)0.0101 (6)0.0077 (6)0.0004 (5)0.0019 (5)0.0002 (5)
C10.0175 (7)0.0110 (7)0.0111 (8)0.0019 (6)0.0007 (6)0.0014 (5)
C20.0196 (7)0.0140 (8)0.0086 (7)0.0004 (6)0.0021 (6)0.0007 (6)
C30.0172 (7)0.0116 (8)0.0130 (7)0.0010 (6)0.0009 (6)0.0009 (6)
C40.0185 (8)0.0093 (7)0.0124 (7)0.0001 (6)0.0007 (6)0.0006 (5)
C50.0213 (7)0.0106 (8)0.0097 (7)0.0001 (6)0.0005 (6)0.0014 (6)
C60.0152 (7)0.0113 (8)0.0098 (7)0.0010 (6)0.0005 (6)0.0003 (6)
C70.0151 (7)0.0120 (7)0.0114 (7)0.0002 (6)0.0007 (6)0.0020 (6)
Geometric parameters (Å, º) top
O1—C11.410 (2)C1—H1A1.0000
O1—H10.8400C3—C41.535 (2)
O2—C41.439 (2)C3—H3A0.9900
O2—H20.8400C3—H3B0.9900
O3—C21.2368 (19)C4—C51.532 (2)
O4—C71.409 (2)C4—H4A1.0000
O4—H40.8400C5—C61.526 (2)
N1—C21.331 (2)C5—H5A0.9900
N1—C31.459 (2)C5—H5B0.9900
N1—C61.4721 (18)C6—C71.542 (2)
C1—C71.528 (2)C6—H61.0000
C1—C21.535 (2)C7—H71.0000
C1—O1—H1109.5C5—C4—C3104.56 (12)
C4—O2—H2109.5O2—C4—H4A111.1
C7—O4—H4109.5C5—C4—H4A111.1
C2—N1—C3127.91 (12)C3—C4—H4A111.1
C2—N1—C6113.83 (12)C6—C5—C4104.01 (12)
C3—N1—C6113.74 (12)C6—C5—H5A111.0
O1—C1—C7112.59 (13)C4—C5—H5A111.0
O1—C1—C2113.15 (12)C6—C5—H5B111.0
C7—C1—C2101.60 (12)C4—C5—H5B111.0
O1—C1—H1A109.7H5A—C5—H5B109.0
C7—C1—H1A109.7N1—C6—C5101.20 (12)
C2—C1—H1A109.7N1—C6—C7102.44 (12)
O3—C2—N1125.51 (15)C5—C6—C7120.32 (12)
O3—C2—C1127.26 (14)N1—C6—H6110.6
N1—C2—C1107.22 (11)C5—C6—H6110.6
N1—C3—C4103.30 (12)C7—C6—H6110.6
N1—C3—H3A111.1O4—C7—C1110.98 (13)
C4—C3—H3A111.1O4—C7—C6114.49 (13)
N1—C3—H3B111.1C1—C7—C6102.87 (12)
C4—C3—H3B111.1O4—C7—H7109.4
H3A—C3—H3B109.1C1—C7—H7109.4
O2—C4—C5111.40 (12)C6—C7—H7109.4
O2—C4—C3107.38 (12)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O1—H1···O2i0.841.982.8190 (15)174
O2—H2···O1ii0.842.503.1745 (15)138
O2—H2···O4iii0.842.252.8589 (15)129
O4—H4···O3iv0.841.842.6636 (15)167
C4—H4A···O4ii1.002.413.3057 (18)148
Symmetry codes: (i) x+1, y1/2, z+2; (ii) x+1, y+1/2, z+1; (iii) x, y+1/2, z+1; (iv) x1, y, z1.

Experimental details

Crystal data
Chemical formulaC7H11NO4
Mr173.17
Crystal system, space groupMonoclinic, P21
Temperature (K)100
a, b, c (Å)4.6983 (3), 14.5424 (10), 5.5271 (4)
β (°) 99.663 (3)
V3)372.28 (4)
Z2
Radiation typeCu Kα
µ (mm1)1.09
Crystal size (mm)0.31 × 0.27 × 0.25
Data collection
DiffractometerBruker Kappa APEXII DUO
diffractometer
Absorption correction
No. of measured, independent and
observed [I > 2σ(I)] reflections
3697, 1229, 1228
Rint0.027
(sin θ/λ)max1)0.596
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.029, 0.073, 1.14
No. of reflections1229
No. of parameters112
No. of restraints1
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.27, 0.41
Absolute structureFlack (1983), 537 Friedel pairs
Absolute structure parameter0.20 (17)

Computer programs: APEX2 (Bruker, 2010), SAINT (Bruker, 2010), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), WinGX (Farrugia,1999) and PLATON (Spek, 2009), publCIF (Westrip, 2010) and PLATON (Spek, 2009).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O1—H1···O2i0.841.982.8190 (15)174
O2—H2···O1ii0.842.503.1745 (15)138
O2—H2···O4iii0.842.252.8589 (15)129
O4—H4···O3iv0.841.842.6636 (15)167
C4—H4A···O4ii1.002.413.3057 (18)148
Symmetry codes: (i) x+1, y1/2, z+2; (ii) x+1, y+1/2, z+1; (iii) x, y+1/2, z+1; (iv) x1, y, z1.
 

Acknowledgements

The authors acknowledge the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), the Coorden­ação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) for financial support. FLO and KRLF were supported by fellowships from CAPES and FAPESP, respectively. RA and FC are recipients of research fellowships from CNPq.

References

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First citationFreire, K. R. L., Tormena, C. F. & Coelho, F. (2011). Synlett, pp. 2059–2063.  Google Scholar
First citationHooft, R. W. W., Straver, L. H. & Spek, A. L. (2008). J. Appl. Cryst. 41, 96–103.  Web of Science CrossRef CAS IUCr Journals Google Scholar
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First citationWestrip, S. P. (2010). J. Appl. Cryst. 43, 920–925.  Web of Science CrossRef CAS IUCr Journals Google Scholar

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