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

Oliveira, F.L.; Freire, K.R.L.; Aparicio, R.; Coelho, F.

doi:10.1107/S1600536812002292

organic compounds

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ISSN: 2056-9890

Volume 68| Part 3| March 2012| Page o586

doi:10.1107/S1600536812002292

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

F. L. Oliveira,^a K. R. L. Freire,^b R. Aparicio ^a ^* and F. Coelho ^b

^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); 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 literature concerning preparation of the title compound, see: Freire et al. (2007 ). Analysis of the absolute structure was also performed using likelihood methods, see: Hooft et al. (2008 ).

Experimental

Crystal data

C₇H₁₁NO₄
M_r = 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)
R_int = 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
Δρ_max = 0.27 e Å⁻³
Δρ_min = −0.41 e Å⁻³
Absolute structure: Flack (1983 ), 537 Friedel pairs
Flack parameter: 0.20 (17)

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	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⋯O3^iv	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); cell refinement: SAINT (Bruker, 2010); data reduction: SAINT; 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.

Supporting information

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536812002292/hb6566sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536812002292/hb6566Isup2.hkl

Supporting information file. DOI: 10.1107/S1600536812002292/hb6566Isup3.cml

checkCIF report

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, ³J_H6,H7 = 7.2 Hz e ³J_H1A,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, v_max): 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, J_H7,H1A 8.8, J_H6,H7 7.2 Hz, 1H, H-7); 4.60 (d, J_H7,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.

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

	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.
	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.
	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

C₇H₁₁NO₄	F(000) = 184
M_r = 173.17	D_x = 1.545 Mg m⁻³
Monoclinic, P2₁	Cu Kα radiation, λ = 1.54178 Å
a = 4.6983 (3) Å	Cell parameters from 1229 reflections
b = 14.5424 (10) Å	θ = 6.1–66.8°
c = 5.5271 (4) Å	µ = 1.09 mm⁻¹
β = 99.663 (3)°	T = 100 K
V = 372.28 (4) Å³	Rectangular block, colorless
Z = 2	0.31 × 0.27 × 0.25 mm

Data collection top

Bruker Kappa APEXII DUO diffractometer	1228 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	R_int = 0.027
Graphite monochromator	θ_max = 66.8°, θ_min = 6.1°
Bruker APEX CCD area–detector scans	h = −5→5
3697 measured reflections	k = −16→16
1229 independent reflections	l = −6→6

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.029	H-atom parameters constrained
wR(F²) = 0.073	w = 1/[σ²(F_o²) + (0.0498P)² + 0.0546P] where P = (F_o² + 2F_c²)/3
S = 1.14	(Δ/σ)_max = 0.012
1229 reflections	Δρ_max = 0.27 e Å⁻³
112 parameters	Δρ_min = −0.41 e Å⁻³
1 restraint	Absolute structure: Flack (1983), 537 Friedel pairs
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.20 (17)

Crystal data top

C₇H₁₁NO₄	V = 372.28 (4) Å³
M_r = 173.17	Z = 2
Monoclinic, P2₁	Cu Kα radiation
a = 4.6983 (3) Å	µ = 1.09 mm⁻¹
b = 14.5424 (10) Å	T = 100 K
c = 5.5271 (4) Å	0.31 × 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 reflections	R_int = 0.027
1229 independent reflections

Refinement top

R[F² > 2σ(F²)] = 0.029	H-atom parameters constrained
wR(F²) = 0.073	Δρ_max = 0.27 e Å⁻³
S = 1.14	Δρ_min = −0.41 e Å⁻³
1229 reflections	Absolute structure: Flack (1983), 537 Friedel pairs
112 parameters	Absolute 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

	x	y	z	U_iso*/U_eq
O1	0.6971 (2)	−0.03528 (7)	0.86162 (19)	0.0163 (3)
H1	0.7222	−0.0594	1.0016	0.024*
O2	0.2633 (2)	0.38620 (8)	0.6676 (2)	0.0167 (3)
H2	0.1802	0.4123	0.5394	0.025*
O3	0.9071 (2)	0.13035 (8)	1.12983 (19)	0.0194 (3)
O4	0.1530 (2)	0.02523 (7)	0.5015 (2)	0.0167 (3)
H4	0.0715	0.0504	0.3714	0.025*
N1	0.5577 (3)	0.20182 (9)	0.8573 (2)	0.0128 (3)
C1	0.5216 (3)	0.04341 (11)	0.8610 (3)	0.0134 (3)
H1A	0.3599	0.0303	0.9528	0.016*
C2	0.6890 (3)	0.12859 (11)	0.9697 (3)	0.0141 (3)
C3	0.6663 (3)	0.29584 (11)	0.8577 (3)	0.0143 (3)
H3A	0.8780	0.2966	0.8633	0.017*
H3B	0.6191	0.3310	0.9992	0.017*
C4	0.5078 (3)	0.33520 (10)	0.6142 (3)	0.0136 (3)
H4A	0.6384	0.3753	0.5346	0.016*
C5	0.4128 (3)	0.25050 (10)	0.4564 (3)	0.0142 (3)
H5A	0.2409	0.2644	0.3318	0.017*
H5B	0.5701	0.2286	0.3721	0.017*
C6	0.3420 (3)	0.17927 (10)	0.6401 (2)	0.0124 (3)
H6	0.1420	0.1887	0.6752	0.015*
C7	0.3995 (3)	0.07635 (12)	0.6019 (3)	0.0132 (3)
H7	0.5501	0.0697	0.4949	0.016*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0237 (5)	0.0097 (6)	0.0144 (5)	0.0043 (5)	0.0003 (4)	0.0025 (5)
O2	0.0219 (5)	0.0113 (6)	0.0152 (5)	0.0040 (4)	−0.0017 (4)	0.0004 (4)
O3	0.0229 (6)	0.0171 (6)	0.0149 (5)	0.0001 (5)	−0.0062 (4)	0.0016 (4)
O4	0.0209 (5)	0.0118 (6)	0.0141 (5)	−0.0016 (4)	−0.0065 (4)	0.0014 (4)
N1	0.0192 (6)	0.0101 (6)	0.0077 (6)	0.0004 (5)	−0.0019 (5)	−0.0002 (5)
C1	0.0175 (7)	0.0110 (7)	0.0111 (8)	0.0019 (6)	0.0007 (6)	0.0014 (5)
C2	0.0196 (7)	0.0140 (8)	0.0086 (7)	−0.0004 (6)	0.0021 (6)	−0.0007 (6)
C3	0.0172 (7)	0.0116 (8)	0.0130 (7)	−0.0010 (6)	−0.0009 (6)	−0.0009 (6)
C4	0.0185 (8)	0.0093 (7)	0.0124 (7)	0.0001 (6)	0.0007 (6)	0.0006 (5)
C5	0.0213 (7)	0.0106 (8)	0.0097 (7)	0.0001 (6)	−0.0005 (6)	0.0014 (6)
C6	0.0152 (7)	0.0113 (8)	0.0098 (7)	0.0010 (6)	−0.0005 (6)	0.0003 (6)
C7	0.0151 (7)	0.0120 (7)	0.0114 (7)	0.0002 (6)	−0.0007 (6)	0.0020 (6)

Geometric parameters (Å, º) top

O1—C1	1.410 (2)	C1—H1A	1.0000
O1—H1	0.8400	C3—C4	1.535 (2)
O2—C4	1.439 (2)	C3—H3A	0.9900
O2—H2	0.8400	C3—H3B	0.9900
O3—C2	1.2368 (19)	C4—C5	1.532 (2)
O4—C7	1.409 (2)	C4—H4A	1.0000
O4—H4	0.8400	C5—C6	1.526 (2)
N1—C2	1.331 (2)	C5—H5A	0.9900
N1—C3	1.459 (2)	C5—H5B	0.9900
N1—C6	1.4721 (18)	C6—C7	1.542 (2)
C1—C7	1.528 (2)	C6—H6	1.0000
C1—C2	1.535 (2)	C7—H7	1.0000

C1—O1—H1	109.5	C5—C4—C3	104.56 (12)
C4—O2—H2	109.5	O2—C4—H4A	111.1
C7—O4—H4	109.5	C5—C4—H4A	111.1
C2—N1—C3	127.91 (12)	C3—C4—H4A	111.1
C2—N1—C6	113.83 (12)	C6—C5—C4	104.01 (12)
C3—N1—C6	113.74 (12)	C6—C5—H5A	111.0
O1—C1—C7	112.59 (13)	C4—C5—H5A	111.0
O1—C1—C2	113.15 (12)	C6—C5—H5B	111.0
C7—C1—C2	101.60 (12)	C4—C5—H5B	111.0
O1—C1—H1A	109.7	H5A—C5—H5B	109.0
C7—C1—H1A	109.7	N1—C6—C5	101.20 (12)
C2—C1—H1A	109.7	N1—C6—C7	102.44 (12)
O3—C2—N1	125.51 (15)	C5—C6—C7	120.32 (12)
O3—C2—C1	127.26 (14)	N1—C6—H6	110.6
N1—C2—C1	107.22 (11)	C5—C6—H6	110.6
N1—C3—C4	103.30 (12)	C7—C6—H6	110.6
N1—C3—H3A	111.1	O4—C7—C1	110.98 (13)
C4—C3—H3A	111.1	O4—C7—C6	114.49 (13)
N1—C3—H3B	111.1	C1—C7—C6	102.87 (12)
C4—C3—H3B	111.1	O4—C7—H7	109.4
H3A—C3—H3B	109.1	C1—C7—H7	109.4
O2—C4—C5	111.40 (12)	C6—C7—H7	109.4
O2—C4—C3	107.38 (12)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	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···O3^iv	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−1/2, −z+2; (ii) −x+1, y+1/2, −z+1; (iii) −x, y+1/2, −z+1; (iv) x−1, y, z−1.

Experimental details

Crystal data
Chemical formula	C₇H₁₁NO₄
M_r	173.17
Crystal system, space group	Monoclinic, P2₁
Temperature (K)	100
a, b, c (Å)	4.6983 (3), 14.5424 (10), 5.5271 (4)
β (°)	99.663 (3)
V (Å³)	372.28 (4)
Z	2
Radiation type	Cu Kα
µ (mm⁻¹)	1.09
Crystal size (mm)	0.31 × 0.27 × 0.25

Data collection
Diffractometer	Bruker Kappa APEXII DUO diffractometer
Absorption correction	–
No. of measured, independent and observed [I > 2σ(I)] reflections	3697, 1229, 1228
R_int	0.027
(sin θ/λ)_max (Å⁻¹)	0.596

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.029, 0.073, 1.14
No. of reflections	1229
No. of parameters	112
No. of restraints	1
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.27, −0.41
Absolute structure	Flack (1983), 537 Friedel pairs
Absolute structure parameter	0.20 (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···A	D—H	H···A	D···A	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···O3^iv	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−1/2, −z+2; (ii) −x+1, y+1/2, −z+1; (iii) −x, y+1/2, −z+1; (iv) x−1, y, z−1.

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.

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