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Acta Crystallogr Sect E Struct Rep OnlineActa Crystallogr Sect E Struct Rep OnlineActa Cryst. EActa Crystallographica Section E: Structure Reports Online1600-5368International Union of Crystallography pv252610.1107/S1600536812018223ACSEBHS1600536812018223Organic Papers(1S,2E,6R,7aR)-2-Benzyl­idene-1,6-dihy­droxy-2,3,5,6,7,7a-hexa­hydro-1H-pyrrolizin-3-one C14H15NO3Oliveira F. L. aFreire K. R. L. bAparicio R. a*Coelho F. ba Laboratory of Structural Biology and Crystallography, Institute of Chemistry, University of Campinas, CP6154, CEP13083-970, Campinas, SP, Brazilb Laboratory of Synthesis of Natural Products and Drugs, Institute of Chemistry, University of Campinas, CP6154, CEP13083-970, Campinas, SP, BrazilCorrespondence e-mail: scott59@example.org 5 2012 28 4 2012 28 4 2012 68 Pt 5 e120500o1572 o1572 17 3 2012 23 4 2012 © Oliveira et al. 20122012This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.A full version of this article is available from Crystallography Journals Online.In the title compound, C14H15NO3, the conformation of the double bond was determined to be E, confirming the result obtained from two-dimensional NMR data. The five-membered rings of the pyrrolizine unit exhibit C-envelope conformations, with C atoms displaced from the mean planes formed by the remaining rings atoms by 0.1468 (15) and 0.5405 (17) Å. The mean planes of these rings (through all ring atoms) have a dihedral angle of 49.03 (10)°. In the crystal, mol­ecules are linked by O—H⋯O hydrogen bonds. The absolute configuration of the mol­ecule was established, as judged by the, as judged by the obtained values for the Hooft and Flack parameters.
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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
 


C14H15NO3



M
r = 245.27

Orthorhombic, 



a = 6.5007 (3) Å


b = 13.6783 (7) Å


c = 13.8382 (7) Å


V = 1230.47 (11) Å3



Z = 4

Cu Kα radiation

μ = 0.77 mm−1



T = 100 K

0.31 × 0.13 × 0.13 mm




Data collection
 


Bruker Kappa APEXII DUO diffractometer

Absorption correction: numerical (SADABS; Bruker, 2010 ▶) T
min = 0.924, T
max = 1.000

32528 measured reflections

2219 independent reflections

2203 reflections with I > 2σ(I)


R
int = 0.034




Refinement
 



R[F
2 > 2σ(F
2)] = 0.037


wR(F
2) = 0.098


S = 1.06

2219 reflections

165 parameters

H-atom parameters constrained

Δρmax = 0.27 e Å−3


Δρmin = −0.23 e Å−3


Absolute structure: Flack (1983 ▶) and Hooft et al. (2008 ▶); Hooft parameter = 0.01(2), 905 Bijvoet pairs

Flack parameter: 0.1 (3)





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/S1600536812018223/pv2526sup1.cif


 Supplementary material file. DOI: 10.1107/S1600536812018223/pv2526Isup2.cml


 Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812018223/pv2526Isup3.hkl


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


 Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: PV2526).

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 (Fig. 1) is a new asymmetric benzyl-pyrrolizidinone which has
been synthesized from a chiral Morita-Baylis-Hillman adduct. It belongs to a
class of compounds with potential pharmacological properties as mediators of
the LFA-1 (lymphocyte function-associated antigen 1) function, particularly as
anti-inflammatory agents and for the treatment of autoimmune diseases
(Baumann, 2007). It has three defined stereocenters and a double bond
with
E configuration. The five membered rings
N1/C3/C2/C1/C7A and N1/C5/C6/C7/C7A of the pyrrolizine moiety exhibit C2- and
C5-envelope conformations, respectively, with C2 and C5 atoms displaced from
the mean-planes formed by the remaining rings atoms by 0.1468 (15) and
0.5405 (17) Å, respectively. The mean planes of these rings have a dihedral
angle of 49.03 (10)°. The configuration of the double bond determined by
X-ray crystallography confirms the two-dimensional-NOESY NMR analysis. The
crystal structure is stabilized by intermolecular hydrogen bonds (Tab. 1
and Fig. 2).


Experimental 
The title compound was prepared using a synthetic sequence previously described
(Freire et al., 2011) and purified by flash silica gel column
chromatography (CH2Cl2:MeOH – solvent gradient: 100:0 to 95:05) to afford
0.14 g (as a white solid) in 76% yield, followed by recrystallization using
the liquid-vapor saturation method. Subsequently, it was dissolved in ethanol
and crystallized under the vapor pressure of ethyl ether (a less polar
liquid), in a closed camera, thus allowing for the slow formation of good
diffracting crystals.


Refinement 
The calculated Flack parameter was F = 0.1 (3) (Flack, 1983). Further
analysis
OF the absolute structure was performed with PLATON (Spek,
2009), using
likelihood methods (Hooft et al., 2008). The calculated value
for the
Hooft parameter was y = 0.01 (2), with a corresponding probability of
1x10-100 for an inverted structure. These results unequivocally indicate
that the absolute structure has been correctly assigned.
All H atoms were placed in calculated positions with O—H = 0.84 Å and C—H = 0.95, 0.99 and 1.00 Å for aryl, methylene and methyne
H-atoms, respectively, and refined in the riding model approximation with
Uiso(H) = 1.5 Ueq(O) or 1.2 Ueq(C).

Figures
Fig. 1. The molecular structure of the title compound with the atom numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. H atoms are presented as small spheres of arbitrary radius.

Fig. 2. A view of the hydrogen bonding interactions (dotted lines) in the crystal structure of the title compound. H atoms non-participating in hydrogen-bonding were omitted for clarity.

Crystal data
C14H15NO3	Dx = 1.324 Mg m−3	
Mr = 245.27	Cu Kα radiation, λ = 1.54178 Å	
Orthorhombic, P212121	Cell parameters from 2219 reflections	
a = 6.5007 (3) Å	θ = 4.6–68.1°	
b = 13.6783 (7) Å	µ = 0.77 mm−1	
c = 13.8382 (7) Å	T = 100 K	
V = 1230.47 (11) Å3	Rectangular, colourless	
Z = 4	0.31 × 0.13 × 0.13 mm	
F(000) = 520		
Data collection
Bruker Kappa APEXII DUO diffractometer	2219 independent reflections	
Radiation source: fine-focus sealed tube	2203 reflections with I > 2σ(I)	
Graphite monochromator	Rint = 0.034	
Bruker APEX CCD area–detector scans	θmax = 68.1°, θmin = 4.6°	
Absorption correction: numerical (SADABS; Bruker, 2010)	h = −7→5	
Tmin = 0.924, Tmax = 1.000	k = −16→16	
32528 measured reflections	l = −16→16	
Refinement
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)] = 0.037	H-atom parameters constrained	
wR(F2) = 0.098	w = 1/[σ2(Fo2) + (0.0574P)2 + 0.2433P] where P = (Fo2 + 2Fc2)/3	
S = 1.06	(Δ/σ)max < 0.001	
2219 reflections	Δρmax = 0.27 e Å−3	
165 parameters	Δρmin = −0.23 e Å−3	
0 restraints	Absolute structure: Flack (1983) and Hooft et al. (2008);
Hooft parameter = 0.01(2), 905 Bijvoet pairs	
Primary atom site location: structure-invariant direct methods	Flack parameter: 0.1 (3)	
Special details
Experimental. [α]D20 + 40 (c 1, MeOH); IR (Film, νmax): 3427, 3195, 2940, 2855, 1668,
1634, 1493, 1424, 1268, 1156, 1067 cm-1; 1H NMR (400 MHz, CD3CN) δ 1.30
(m, J = 13.8, 9.1, 5.4 Hz, 1H, H-14 A), 2.38 (m, J = 13.8, 6.8 Hz, 1H, H-14B), 3.27 (dd, J = 12.3, 6.1 Hz, 1H, H-2 A), 3.56 (dd,
J = 12.3, 3.3 Hz, 1H, H-2B), 3.69 (ddd, J = 9.1, 7.4, 1.8 Hz,
1H, H-10), 4.47 (qd, J = 6.1, 3.3 Hz, 1H, H-1 A), 4.91 (dd, J =
1.8 Hz, 1H, H-11), 7.35 (d, J = 2.1 Hz, 1H, H-5), 7.41 (m, 3H, Ph),
7.79 (m, 2H, Ph); 13C NMR (62.5 MHz, (CD3)2CO) δ 38.1, 52.1, 68.2,
70.1, 72.0, 129.2, 130.3, 131.3, 134.1, 134.2, 137.1, 172.1; HRMS (ESI-TOF)
Calcd. for C14H16NO3 [M + H]+ 246.1130. Found 246.1168.	
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)
	x	y	z	Uiso*/Ueq		
O1	0.2407 (3)	0.95636 (13)	0.17238 (19)	0.1020 (7)		
H1	0.1725	1.0026	0.1962	0.153*		
O2	0.52812 (19)	0.71064 (10)	0.18954 (10)	0.0546 (3)		
O3	−0.14247 (18)	0.65007 (11)	0.28956 (12)	0.0615 (4)		
H3	−0.2555	0.6653	0.2643	0.092*		
N1	0.2098 (2)	0.75095 (9)	0.13314 (9)	0.0364 (3)		
C6	0.1266 (3)	0.91174 (13)	0.09912 (14)	0.0478 (4)		
H1A	0.0930	0.9587	0.0460	0.057*		
C5	0.2537 (3)	0.82646 (13)	0.06255 (12)	0.0465 (4)		
H2A	0.2099	0.8063	−0.0030	0.056*		
H2B	0.4021	0.8428	0.0614	0.056*		
C3	0.3405 (2)	0.71615 (11)	0.20026 (12)	0.0364 (3)		
C2	0.2186 (2)	0.68831 (11)	0.28681 (11)	0.0336 (3)		
C4	0.3095 (2)	0.64180 (11)	0.36077 (11)	0.0381 (3)		
H5	0.4483	0.6237	0.3490	0.046*		
C8	0.2326 (3)	0.61406 (11)	0.45626 (11)	0.0389 (4)		
C13	0.3573 (3)	0.55253 (13)	0.51150 (13)	0.0498 (4)		
H7	0.4864	0.5321	0.4864	0.060*		
C12	0.2964 (4)	0.52072 (15)	0.60216 (14)	0.0635 (6)		
H8	0.3822	0.4779	0.6382	0.076*		
C11	0.1114 (4)	0.55125 (15)	0.63990 (13)	0.0631 (6)		
H9	0.0687	0.5294	0.7019	0.076*		
C7A	−0.0026 (2)	0.75856 (12)	0.16618 (11)	0.0378 (3)		
H10	−0.0881	0.7114	0.1283	0.045*		
C1	0.0020 (2)	0.72470 (11)	0.27237 (11)	0.0364 (3)		
H11	−0.0253	0.7814	0.3162	0.044*		
C10	−0.0113 (4)	0.61354 (15)	0.58734 (13)	0.0603 (5)		
H12	−0.1380	0.6353	0.6140	0.072*		
C9	0.0468 (3)	0.64509 (14)	0.49607 (13)	0.0498 (4)		
H13	−0.0401	0.6879	0.4607	0.060*		
C7	−0.0656 (3)	0.86200 (15)	0.13809 (16)	0.0584 (5)		
H14A	−0.1744	0.8603	0.0880	0.070*		
H14B	−0.1189	0.8977	0.1951	0.070*		
Atomic displacement parameters (Å2)
	U11	U22	U33	U12	U13	U23	
O1	0.0789 (13)	0.0675 (10)	0.159 (2)	0.0143 (9)	−0.0431 (13)	−0.0432 (12)	
O2	0.0280 (6)	0.0762 (9)	0.0597 (7)	0.0084 (6)	0.0039 (5)	0.0184 (7)	
O3	0.0281 (6)	0.0713 (9)	0.0852 (10)	−0.0097 (6)	−0.0096 (6)	0.0430 (8)	
N1	0.0322 (6)	0.0392 (6)	0.0379 (6)	0.0041 (5)	−0.0002 (5)	0.0048 (5)	
C6	0.0442 (9)	0.0423 (8)	0.0570 (10)	0.0035 (7)	−0.0013 (8)	0.0138 (8)	
C5	0.0410 (10)	0.0574 (10)	0.0411 (8)	0.0042 (7)	0.0057 (7)	0.0141 (7)	
C3	0.0278 (8)	0.0392 (8)	0.0421 (8)	0.0037 (6)	−0.0011 (6)	0.0029 (6)	
C2	0.0292 (7)	0.0355 (7)	0.0361 (7)	−0.0007 (6)	−0.0034 (6)	0.0018 (6)	
C4	0.0309 (7)	0.0418 (8)	0.0418 (8)	−0.0003 (6)	−0.0042 (6)	0.0033 (7)	
C8	0.0451 (9)	0.0348 (7)	0.0367 (8)	−0.0039 (7)	−0.0068 (7)	−0.0012 (6)	
C13	0.0540 (11)	0.0485 (10)	0.0469 (9)	0.0012 (8)	−0.0085 (8)	0.0047 (8)	
C12	0.0888 (16)	0.0570 (11)	0.0448 (10)	−0.0003 (11)	−0.0128 (11)	0.0131 (9)	
C11	0.0951 (16)	0.0564 (11)	0.0377 (9)	−0.0114 (11)	0.0023 (10)	0.0015 (8)	
C7A	0.0255 (7)	0.0454 (8)	0.0425 (8)	−0.0020 (6)	−0.0051 (6)	0.0094 (6)	
C1	0.0283 (7)	0.0387 (7)	0.0420 (8)	0.0030 (6)	0.0001 (6)	0.0077 (6)	
C10	0.0782 (14)	0.0562 (10)	0.0464 (9)	0.0000 (11)	0.0177 (10)	−0.0107 (8)	
C9	0.0599 (11)	0.0458 (9)	0.0437 (9)	0.0058 (8)	0.0036 (8)	−0.0026 (7)	
C7	0.0440 (10)	0.0594 (11)	0.0717 (12)	0.0174 (8)	0.0097 (9)	0.0263 (10)	
Geometric parameters (Å, º)
O1—C6	1.397 (3)	C8—C9	1.393 (3)	
O1—H1	0.8400	C8—C13	1.397 (2)	
O2—C3	1.231 (2)	C13—C12	1.386 (3)	
O3—C1	1.4074 (19)	C13—H7	0.9500	
O3—H3	0.8400	C12—C11	1.376 (4)	
N1—C3	1.346 (2)	C12—H8	0.9500	
N1—C5	1.450 (2)	C11—C10	1.375 (3)	
N1—C7A	1.458 (2)	C11—H9	0.9500	
C6—C5	1.517 (2)	C7A—C7	1.524 (2)	
C6—C7	1.521 (3)	C7A—C1	1.541 (2)	
C6—H1A	1.0000	C7A—H10	1.0000	
C5—H2A	0.9900	C1—H11	1.0000	
C5—H2B	0.9900	C10—C9	1.387 (3)	
C3—C2	1.486 (2)	C10—H12	0.9500	
C2—C4	1.342 (2)	C9—H13	0.9500	
C2—C1	1.507 (2)	C7—H14A	0.9900	
C4—C8	1.463 (2)	C7—H14B	0.9900	
C4—H5	0.9500			
				
C6—O1—H1	109.5	C8—C13—H7	119.4	
C1—O3—H3	109.5	C11—C12—C13	119.9 (2)	
C3—N1—C5	126.33 (14)	C11—C12—H8	120.1	
C3—N1—C7A	113.99 (12)	C13—C12—H8	120.1	
C5—N1—C7A	110.30 (12)	C10—C11—C12	119.62 (18)	
O1—C6—C5	106.77 (16)	C10—C11—H9	120.2	
O1—C6—C7	111.99 (19)	C12—C11—H9	120.2	
C5—C6—C7	102.82 (14)	N1—C7A—C7	103.95 (13)	
O1—C6—H1A	111.6	N1—C7A—C1	105.03 (12)	
C5—C6—H1A	111.6	C7—C7A—C1	121.85 (16)	
C7—C6—H1A	111.6	N1—C7A—H10	108.4	
N1—C5—C6	102.46 (13)	C7—C7A—H10	108.4	
N1—C5—H2A	111.3	C1—C7A—H10	108.4	
C6—C5—H2A	111.3	O3—C1—C2	111.20 (12)	
N1—C5—H2B	111.3	O3—C1—C7A	111.48 (13)	
C6—C5—H2B	111.3	C2—C1—C7A	104.12 (12)	
H2A—C5—H2B	109.2	O3—C1—H11	110.0	
O2—C3—N1	124.34 (16)	C2—C1—H11	110.0	
O2—C3—C2	127.58 (15)	C7A—C1—H11	110.0	
N1—C3—C2	108.08 (12)	C11—C10—C9	121.1 (2)	
C4—C2—C3	120.10 (14)	C11—C10—H12	119.5	
C4—C2—C1	132.00 (14)	C9—C10—H12	119.5	
C3—C2—C1	107.86 (12)	C10—C9—C8	120.10 (19)	
C2—C4—C8	131.40 (15)	C10—C9—H13	120.0	
C2—C4—H5	114.3	C8—C9—H13	120.0	
C8—C4—H5	114.3	C6—C7—C7A	106.55 (14)	
C9—C8—C13	118.05 (16)	C6—C7—H14A	110.4	
C9—C8—C4	125.05 (15)	C7A—C7—H14A	110.4	
C13—C8—C4	116.90 (16)	C6—C7—H14B	110.4	
C12—C13—C8	121.3 (2)	C7A—C7—H14B	110.4	
C12—C13—H7	119.4	H14A—C7—H14B	108.6	
				
C3—N1—C5—C6	−109.15 (17)	C3—N1—C7A—C7	130.55 (16)	
C7A—N1—C5—C6	34.96 (17)	C5—N1—C7A—C7	−18.33 (18)	
O1—C6—C5—N1	81.68 (19)	C3—N1—C7A—C1	1.52 (18)	
C7—C6—C5—N1	−36.33 (18)	C5—N1—C7A—C1	−147.35 (13)	
C5—N1—C3—O2	−31.5 (3)	C4—C2—C1—O3	−52.6 (2)	
C7A—N1—C3—O2	−174.55 (16)	C3—C2—C1—O3	129.73 (14)	
C5—N1—C3—C2	147.63 (14)	C4—C2—C1—C7A	−172.77 (17)	
C7A—N1—C3—C2	4.63 (18)	C3—C2—C1—C7A	9.56 (16)	
O2—C3—C2—C4	−7.9 (3)	N1—C7A—C1—O3	−126.78 (14)	
N1—C3—C2—C4	172.96 (14)	C7—C7A—C1—O3	115.79 (17)	
O2—C3—C2—C1	170.10 (17)	N1—C7A—C1—C2	−6.80 (16)	
N1—C3—C2—C1	−9.04 (17)	C7—C7A—C1—C2	−124.23 (16)	
C3—C2—C4—C8	173.90 (15)	C12—C11—C10—C9	1.0 (3)	
C1—C2—C4—C8	−3.5 (3)	C11—C10—C9—C8	−0.3 (3)	
C2—C4—C8—C9	−10.3 (3)	C13—C8—C9—C10	−1.1 (3)	
C2—C4—C8—C13	170.38 (17)	C4—C8—C9—C10	179.60 (17)	
C9—C8—C13—C12	1.8 (3)	O1—C6—C7—C7A	−88.1 (2)	
C4—C8—C13—C12	−178.83 (17)	C5—C6—C7—C7A	26.1 (2)	
C8—C13—C12—C11	−1.1 (3)	N1—C7A—C7—C6	−5.9 (2)	
C13—C12—C11—C10	−0.3 (3)	C1—C7A—C7—C6	112.09 (18)	
Hydrogen-bond geometry (Å, º)
D—H···A	D—H	H···A	D···A	D—H···A	
O1—H1···O3i	0.84	2.04	2.776 (2)	147	
O3—H3···O2ii	0.84	1.85	2.6810 (17)	168	
Symmetry codes: (i) −x, y+1/2, −z+1/2; (ii) x−1, y, z.

Table 1 Hydrogen-bond geometry (Å, °)
D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A	
O1—H1⋯O3i	0.84	2.04	2.776 (2)	147	
O3—H3⋯O2ii	0.84	1.85	2.6810 (17)	168	
Symmetry codes: (i) ; (ii) .
==== Refs
References
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