(1S,2E,6R,7aR)-1,6-Dihy­droxy-2-(4-nitro­benzyl­idene)-2,3,5,6,7,7a-hexa­hydro-1H-pyrrolizin-3-one

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

doi:10.1107/S1600536812018235

. 2012 Apr 28;68(Pt 5):o1570–o1571. doi: 10.1107/S1600536812018235

(1S,2E,6R,7aR)-1,6-Dihydroxy-2-(4-nitrobenzylidene)-2,3,5,6,7,7a-hexahydro-1H-pyrrolizin-3-one

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

PMCID: PMC3344666 PMID: 22590428

Abstract

The crystal structure of the title compound, C₁₄H₁₄N₂O₅, contains two distinct conformers in the asymmetric unit. The compound has three defined stereocenters, two of them contiguous, and a C=C double bond with an E conformation. The stereocenters exhibit the same chirality in both conformers, with significant differences in the conformation of the five-membered rings of the pyrrolizine unit (both either in a twist or in an envelope form) and in the dihedral angles between the corresponding mean planes and the benzene rings. A prominent feature is a change from almost coplanar rings in one conformer to a new conformation in the second conformer, in which the mean plane of a five-membered ring is almost perpendicular to the benzene ring, with a dihedral angle 87.19 (8)°; the corresponding angle in the first conformer is 14.02 (10)°. In the crystal, molecules are linked by O—H⋯O and C—H⋯O hydrogen bonds. Crystallographic data were essential to confirm the configuration of the double bond, which was unclear from the available two-dimensional NMR data. In addition, reliable Flack and Hooft parameters were obtained, allowing for the correct absolute structure to be determined.

Related literature

For the preparation of the title compound, see: Freire et al. (2011 ▶). For the use of this type of compound as LFA-1 (Lymphocyte Function-Associated Antigen-1) inhibitors, see: Baumann (2007 ▶). For related structures, see: Oliveira et al. (2012a ▶,b ▶).

Experimental

Crystal data

C₁₄H₁₄N₂O₅
M _r = 290.27
Monoclinic,
a = 6.8289 (6) Å
b = 7.0433 (6) Å
c = 26.618 (3) Å
β = 92.335 (4)°
V = 1279.2 (2) Å³
Z = 4
Cu Kα radiation
μ = 0.98 mm⁻¹
T = 100 K
0.39 × 0.23 × 0.06 mm

Data collection

Bruker Kappa APEXII DUO diffractometer
Absorption correction: numerical (SADABS; Bruker, 2010 ▶) T _min = 0.844, T _max = 1.000
41060 measured reflections
4038 independent reflections
3986 reflections with I > 2σ(I)
R _int = 0.037

Refinement

R[F ² > 2σ(F ²)] = 0.025
wR(F ²) = 0.067
S = 1.01
4038 reflections
383 parameters
1 restraint
H-atom parameters constrained
Δρ_max = 0.15 e Å⁻³
Δρ_min = −0.16 e Å⁻³
Absolute structure: Flack (1983 ▶) and Hooft et al. (2008 ▶); Hooft parameter = 0.04(4), 1539 Bijvoet pairs
Flack parameter: 0.03 (11)

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: PLATON (Spek, 2009 ▶); software used to prepare material for publication: publCIF (Westrip, 2010 ▶).

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812018235/pv2525sup1.cif

e-68-o1570-sup1.cif^{(36.4KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812018235/pv2525Isup2.hkl

e-68-o1570-Isup2.hkl^{(197.9KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536812018235/pv2525Isup3.cml

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

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O3—H3⋯O1′ⁱ	0.82	1.93	2.7303 (14)	166
O1—H1A⋯O2ⁱⁱ	0.82	1.89	2.6993 (15)	169
O3′—H3′⋯O3ⁱⁱⁱ	0.82	1.95	2.7585 (15)	171
O1′—H1A′⋯O3′^iv	0.82	1.93	2.7451 (15)	174
C1′—H1′⋯O2′ⁱⁱ	0.98	2.52	3.3655 (17)	144
C1′—H1′⋯O5′^v	0.98	2.55	3.3242 (19)	136
C10—H10⋯O1^vi	0.93	2.54	3.126 (2)	121
C12′—H12′⋯O3′^vii	0.93	2.57	3.5014 (18)	174
C13—H13⋯O4ⁱ	0.93	2.51	3.2644 (19)	138
C13′—H13′⋯O5′ⁱ	0.93	2.51	3.1160 (18)	123

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) ; (v) ; (vi) ; (vii) .

Acknowledgments

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 bursaries from CAPES and CNPq, respectively. KRLF is currently a FAPESP post-doctoral fellow. RA and FC are recipients of research grants from CNPq.

supplementary crystallographic information

Comment

The title compound, a new asymmetric benzyl-pyrrolizidinone, has been prepared from a Morita-Baylis-Hillman adduct using a straight forward synthetic sequence developed in our laboratory (Freire et al., 2011). It can be used as a prototype to design new mediators of the activity of LFA-1 (lymphocyte function-associated antigen 1), with potential applications in the treatment of autoimmune diseases and as anti-inflammatory drugs (Baumann, 2007). The title compound has three defined stereocenters, two of them contiguous, and a double bond with E configuration, an information which was not clear from two-dimensional-NOESY NMR studies. A crystal structure determination of the titlte compound has allowed us to establish its correct configuration, which is reported in this article.

In the crystal structure of the title compound, an asymmetric unit contains two distinct conformers, molecule 1 (Fig. 1) and molecule 2 (Fig. 2), whose stereocenters exhibit the same chirality. In molecule 1, the five membered rings N1/C3/C2/C1/C7A and N1/C5/C6/C7/C7A of the pyrrolizine moiety exhibit C1- and C7-envelope conformations, respectively, with C1 and C7 atoms displaced from the mean-planes formed by the remaining rings atoms by 0.3194 (14) and 0.592 (2) Å, respectively. The mean planes of these rings have a dihedral angle of 23.47 (10)°, and are almost coplanar to the benzene ring, with which they form dihedral angles of 24.52 (9)° and 14.02 (10)°, respectively. The molecule 2 exhibits the rings N1'/C7A'/C1'/C2'/C3' and N1'/C7A'/C7'/C6'/C5' in a twisted conformation on C7A'-C1' and N1'-C7A', respectively, with a dihedral angle between their mean planes equal to 58.07 (8)°. The dihedral angle between the mean planes of the ring N1'/C7A'/C1'/C2'/C3' and the benzene ring is 34.75 (7)°. The ring N1'/C7A'/C7'/C6'/C5' is almost perpendicular to the latter with a corresponding angle equal to 87.19 (8)°. The atom C1' lies 0.3200 (14) Å out of the plane formed by the rest of the ring atoms (N1'/C7A'/C2'/C3'). The corresponding measurement for the atom C7A' in relation to the mean plane formed by the other atoms in the ring (N1'/C7'/C6'/C5') is 0.4771 (13) Å. In the crystal, the molecules are held together by intermolecular hydrogen bonds (Tab. 1 and Fig. 3).

Experimental

The title compound was prepared by a synthetic sequence recently described in the literature (Freire et al., 2011) and purified by flash silica gel column chromatography (CH₂Cl₂ : MeOH – solvent gradient: 100:0 to 95:05) to afford 0.07 g (as a white solid) in 83% yield. It was then recrystallized using the liquid-vapor saturation method, dissolved in ethanol and crystallized subject to the vapor pressure of a second less polar liquid (ethyl ether), in a closed camera, providing the slow formation of crystals.