Supra­molecular structure of racemic 5-hydr­oxy-4-(4-methoxy­phen­yl)-10-oxa-4-aza­tricyclo­[5.2.1.0^2,6]dec-8-en-3-one

The structure of the title compound, C₁₅H₁₅NO₄, comprises a racemic mixture of chiral mol­ecules containing five stereogenic centres. The cyclo­hexane ring tends towards a boat conformation and the two tetra­hydro­furan rings adopt envelope conformations. Mol­ecules are linked into sheets parallel to (100) by a combination of O—H...O, C—H...O and C—H...π hydrogen bonds, leading to a two-dimensional supra­molecular structure.

S1. Comment

The derivatives of exo-5,6-dehydronorcantharidin are of great pharmacological interest and have attracted considerable attention (Abel et al., 1996; Deng et al., 2005). Furthermore, molecules of this type containing nitrogen have become a hot topic in heterocyclic chemistry because of their antitumour, antiviral, analgesic, sedative and fungicidal activities (Salvati et al., 2005). We therefore become interested in the synthesis of the cantharidin analogue (II), with the possibility that biological activity is modified in the bicyclic imide systems. Compound (II) is generated from (I) in a single synthetic reduction by using Na(BH₄). We report here the synthesis and the crystal structure of (II).

The regiochemistry of (II) was established by ¹H and C NMR spectroscopy, and the diagnostic spin–spin interactions were identified with the aid of HH COSY experiments. The structure determination of (II) confirmed this connectivity and also established the exoposition with bridge H atoms of the molecule [please clarify]. The molecules of (II) are chiral, with five stereogenic centres at atoms C1, C2, C3, C6 and C7. Compound (II) crystallizes as a racemic mixture in space group P2₁/c. The reference molecule was selected to have S, S, R, S and R configurations at atoms C1, C2, C3, C6 and C7, respectively. Hence the racemic mixture consists of molecules whose configurations are 1S,2S,3R,6S,7R and 1R,2R,3S,6R,7S. The inter-bridgehead angles O3—C6—C7 and O3—C3—C2 of 100.44 (17) and 101.04 (16)°, respectively, are contracted with respect to the tetrahedral value, as is the C6—O3—C3 angle of 95.59 (15)°. The cyclohexane ring (C2–C7) adopts a boat conformation. The tetrahydrofuran rings (O3/C3/C2/C7/C6 and O3/C3/C4/C5/C6) have an envelope conformation with atom O3 as the flap atom, with puckering parameters (Cremer & Pople, 1975) of Q = 0.590 (2) Å, ϕ = 180.5 (2)°, Q = 0.508 (2) Å and ϕ = 359.4 (3)°, respectively. The maximum deviations of atom O3 from the planes defined by the remaining four atoms are 0.840 (1) and 0.755 (1) Å, respectively. The dihedral angle between the phenyl and imide rings is 29.28 (12)°. The methoxy substituent is approximately coplanar with the attached phenyl ring. The N—C_aryl bond length is 1.428 (3) Å and is comparable to those found in previously reported structures (Trujillo-Ferrara et al., 2004; Miller et al., 2000; Ellis & Spek, 2001).

The supramolecular structure of (II) is composed of sheets generated by a combination of O—H···O, C—H···O and C—H···π hydrogen bonds (Table 1). The formation of the sheet is analyzed in terms of two different low-dimensional substructures. The first substructure is built using the O—H···O and C—H···π hydrogen bonds, where atoms O1 and C7 in the molecule at (x, y, z) act as hydrogen-bond donors, respectively, to atom O2 and the C9–C14 ring, both in the molecule at (-x + 1, y + 1/2, -z + 3/2), so forming C(6) (Bernstein et al., 1995) chains running parallel to the [010] direction (Fig. 2). The chains include only the molecules of 1S,2S,3R,6S,7R configuration. In the second substructure, atom C1 in the molecule at (x, y, z) (1S,2S,3R,6S,7R) acts as a hydrogen-bond donor to atom O3 in the molecule at (-x + 1, -y + 1, -z + 1) (1R,2R,3S,6R,7S), leading to a centrosymmetric R₂²(10) dimer centered at (1/2, 1/2, 1/2) (Fig. 3). The combination of these interactions generates a sheet parallel to (100). There are no direction-specific interactions between the sheets, so the supramolecular structure of the title compound is two-dimensional (Fig. 4).

Related literature

For related literature, see: Abel et al. (1996); Bernstein et al. (1995); Cremer & Pople (1975); Deng et al. (2005); Ellis & Spek (2001); Hubert et al. (1975); Miller et al. (2000); Salvati et al. (2005); Trujillo-Ferrara et al. (2004).

S2. Experimental

The general synthetics procedure is described by Hubert et al. (1975). N-(4-Methoxyphenyl)-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboximide, (I) (0.77 g, 2.84 mmol), prepared from furan and N-(4-methoxyphenyl)maleimide, was reduced in ethanol solution (250 ml) with 0.94 g of Na(BH₄) added in small portions (at intervals of 15 min) at 252 K over a period of 2 h. The excess of Na(BH₄) was destroyed in 15–30 min at 5 K above the reaction temperature by adding aqueous HCl (2 mol dm^-3) until the pH reached 3.0. The mixture was stirred for an additional 45–60 min at the same temperature and poured into water. After extraction with dichloromethane, the organic layer was separated, dried over Na₂(SO₄) and filtered; the solvent was removed under reduced pressure to give a white solid that was purified by column chromatography [silica gel, n-hexane/ethyl acetate (1:2, v/v)] to give white crystals in 84% yield.

NMR (DMSO): δ(H) 2.11–2.13 (d, J = 7.02 Hz, 1H, H₂), 2.73–2.75 (d, J = 7.02 Hz, 1H, H₆), 3.72 (s, 3H, OCH₃), 4.97 (s, 1H, H₁), 5.10 (s, 1H, H₇), 5.25–5.27 (d, J = 7.8 Hz, 1H, H₅), 6.36–6.38 (d, J = 7.8 Hz, 1H, OH exchange with D₂O), 6.44–6.48 (m, 2H, H₈ and H₉), 6.90–6.92 (d, J = 9.36 Hz, 2H, aromatic), 7.36–7.39 (d, J = 9.36 Hz, 2H, aromatic); δ(C) 47.42 (C₆), 49.38 (C₂), 55.72 (OCH₃), 81.35 (C₇), 82.56 (C₁), 88.21 (C₅), 114.84 (Car), 127.08 (Car), 136.80 (C₈ and C₉), 137.01 (Cq—N). FT–IR (KBr): ν 3347 (OH), 3074, 3021, 2954, 2934 and 2833, 1672 (C═O), 1609 and 1513 (aromatic, C═C), 1445, 1414, 1306, 1252 (C–OCH₃), 1182 (C—O stretching), 1036 (C—N), 829 cm^-1.

S3. Refinement

All H atoms bonded to C atoms were treated as riding atoms, with C—H distances in the range 0.93–0.98 Å and with U_iso(H) = kU_eq(C), where k = 1.5 for the methyl group and 1.2 for all other H atoms. The position of the hydroxy H atom was obtained from a difference map, and its parameters were freely refined.

Computing details

Data collection: X-AREA (Stoe & Cie, 2002); cell refinement: X-AREA (Stoe & Cie, 2002); data reduction: X-RED32 (Stoe & Cie, 2002); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEPIII (Burnett & Johnson, 1996) and PLATON (Spek, 2003); software used to prepare material for publication: WinGX (Farrugia, 1999).

Figures

	Fig. 1. The molecular structure of (II), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.
	Fig. 2. Part of the crystal structure of (II), showing the formation of C(6) chains running parallel to [010]. For the sake of clarity, H atoms not involved in the motifs shown have been omitted. [Symmetry codes: (i) -x + 1, y + 1/2, - z + 3/2; (ii) -x + 1, y - 1/2, -z + 3/2.]
	Fig. 3. Part of the crystal structure of (II), showing the formation of an R2^2(10) dimer centred at (1/2, 1/2, 1/2). For the sake of clarity, H atoms not involved in the motifs shown have been omitted. [Symmetry codes: (iii) -x + 1, -y + 1, -z + 1.]
	Fig. 4. A stereoview of part of the crystal structure of (II), showing the formation of a hydrogen-bonded sheet parallel to (100). For the sake of clarity, H atoms not involved in the motifs shown have been omitted.

5-hydroxy-4-(4-methoxyphenyl)-10-oxa- 4-azatricyclo[5.2.1.0^2,6]dec-8-en-3-one

Crystal data

C15H15NO4	F(000) = 576
Mr = 273.28	Dx = 1.363 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 8698 reflections
a = 11.2076 (11) Å	θ = 2.2–27.9°
b = 8.4910 (7) Å	µ = 0.10 mm^−1
c = 14.1867 (15) Å	T = 293 K
β = 99.457 (8)°	Prismatic stick, colorless
V = 1331.7 (2) Å^3	0.60 × 0.32 × 0.05 mm
Z = 4

Data collection

Stoe IPDSII diffractometer	2600 independent reflections
Radiation source: fine-focus sealed tube	1497 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.070
Detector resolution: 6.67 pixels mm^-1	θmax = 26.0°, θmin = 2.8°
rotation method scans	h = −13→13
Absorption correction: integration (X-RED32; Stoe & Cie, 2002)	k = −10→10
Tmin = 0.952, Tmax = 0.993	l = −17→17
9348 measured reflections

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.046	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.105	H atoms treated by a mixture of independent and constrained refinement
S = 0.95	w = 1/[σ^2(Fo^2) + (0.0472P)^2] where P = (Fo^2 + 2Fc^2)/3
2600 reflections	(Δ/σ)max < 0.001
185 parameters	Δρmax = 0.14 e Å^−3
0 restraints	Δρmin = −0.16 e Å^−3

Special details

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 (Ų)

	x	y	z	Uiso*/Ueq
C1	0.4207 (2)	0.7677 (2)	0.58436 (14)	0.0476 (5)
H1	0.3926	0.6872	0.5363	0.057*
C2	0.55500 (19)	0.7981 (2)	0.58383 (14)	0.0480 (5)
H2	0.5707	0.9084	0.5697	0.058*
C3	0.6123 (2)	0.6838 (2)	0.51904 (15)	0.0549 (6)
H3	0.5661	0.6698	0.4547	0.066*
C4	0.7415 (2)	0.7338 (3)	0.52216 (18)	0.0653 (7)
H4	0.7744	0.7852	0.4745	0.078*
C5	0.7997 (2)	0.6883 (3)	0.60845 (19)	0.0655 (6)
H5	0.8813	0.7006	0.6330	0.079*
C6	0.7044 (2)	0.6135 (2)	0.65641 (16)	0.0558 (6)
H6	0.7349	0.5411	0.7086	0.067*
C7	0.6221 (2)	0.7482 (2)	0.68316 (14)	0.0499 (5)
H7	0.6686	0.8348	0.7170	0.060*
C8	0.5260 (2)	0.6884 (2)	0.73519 (15)	0.0510 (5)
C9	0.3055 (2)	0.6507 (2)	0.70667 (15)	0.0481 (5)
C10	0.2817 (2)	0.6759 (2)	0.79729 (16)	0.0590 (6)
H10	0.3375	0.7300	0.8413	0.071*
C11	0.1757 (2)	0.6219 (3)	0.82413 (17)	0.0653 (7)
H11	0.1611	0.6383	0.8860	0.078*
C12	0.0916 (2)	0.5435 (3)	0.75853 (18)	0.0631 (6)
C13	0.1142 (2)	0.5210 (3)	0.66735 (19)	0.0681 (7)
H13	0.0574	0.4692	0.6228	0.082*
C14	0.2197 (2)	0.5741 (3)	0.64107 (16)	0.0594 (6)
H14	0.2337	0.5586	0.5789	0.071*
C15	−0.0454 (3)	0.5065 (4)	0.8657 (2)	0.0981 (10)
H15A	−0.1215	0.4569	0.8692	0.147*
H15B	−0.0520	0.6177	0.8760	0.147*
H15C	0.0160	0.4631	0.9138	0.147*
N1	0.41634 (17)	0.70217 (19)	0.67952 (11)	0.0489 (4)
O1	0.34588 (15)	0.89990 (18)	0.56653 (11)	0.0569 (4)
O2	0.54368 (16)	0.63113 (19)	0.81618 (11)	0.0690 (5)
O3	0.62555 (14)	0.54348 (15)	0.57720 (10)	0.0576 (4)
O4	−0.01544 (17)	0.4810 (3)	0.77786 (14)	0.0877 (6)
H1A	0.375 (3)	0.975 (4)	0.607 (2)	0.098 (10)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0582 (15)	0.0412 (10)	0.0425 (10)	−0.0002 (9)	0.0053 (9)	0.0036 (8)
C2	0.0541 (15)	0.0391 (10)	0.0501 (12)	−0.0028 (9)	0.0065 (10)	0.0068 (9)
C3	0.0619 (16)	0.0550 (12)	0.0472 (12)	0.0018 (11)	0.0072 (10)	0.0024 (10)
C4	0.0659 (18)	0.0617 (14)	0.0714 (16)	0.0013 (12)	0.0205 (13)	0.0007 (12)
C5	0.0530 (16)	0.0598 (14)	0.0829 (17)	0.0040 (12)	0.0089 (13)	−0.0055 (13)
C6	0.0604 (16)	0.0470 (11)	0.0558 (13)	0.0020 (10)	−0.0032 (11)	0.0015 (10)
C7	0.0564 (15)	0.0406 (10)	0.0495 (12)	−0.0041 (9)	−0.0003 (10)	−0.0033 (9)
C8	0.0645 (16)	0.0389 (10)	0.0479 (12)	0.0003 (10)	0.0046 (11)	0.0007 (9)
C9	0.0567 (15)	0.0397 (10)	0.0481 (12)	0.0019 (9)	0.0088 (10)	0.0050 (9)
C10	0.0690 (17)	0.0536 (13)	0.0550 (14)	−0.0013 (11)	0.0118 (12)	−0.0017 (10)
C11	0.0760 (19)	0.0684 (14)	0.0559 (14)	0.0103 (13)	0.0236 (13)	0.0061 (11)
C12	0.0558 (17)	0.0645 (14)	0.0698 (17)	0.0027 (12)	0.0126 (12)	0.0130 (12)
C13	0.0618 (18)	0.0724 (15)	0.0691 (16)	−0.0066 (13)	0.0077 (13)	−0.0015 (13)
C14	0.0633 (17)	0.0625 (13)	0.0517 (13)	−0.0025 (12)	0.0075 (11)	−0.0008 (11)
C15	0.075 (2)	0.122 (3)	0.106 (2)	0.0089 (18)	0.0394 (18)	0.021 (2)
N1	0.0550 (12)	0.0463 (9)	0.0439 (9)	−0.0016 (8)	0.0039 (8)	0.0057 (8)
O1	0.0605 (11)	0.0502 (9)	0.0569 (9)	0.0054 (8)	0.0004 (8)	0.0074 (7)
O2	0.0776 (13)	0.0757 (10)	0.0506 (9)	0.0044 (8)	0.0016 (8)	0.0161 (8)
O3	0.0663 (11)	0.0412 (8)	0.0618 (9)	−0.0013 (7)	0.0006 (8)	−0.0064 (7)
O4	0.0649 (13)	0.1096 (15)	0.0913 (14)	−0.0064 (11)	0.0204 (11)	0.0186 (12)

Geometric parameters (Å, º)

C1—O1	1.399 (2)	C8—O2	1.233 (2)
C1—N1	1.469 (2)	C8—N1	1.353 (3)
C1—C2	1.528 (3)	C9—C10	1.372 (3)
C1—H1	0.9800	C9—C14	1.385 (3)
C2—C7	1.543 (3)	C9—N1	1.428 (3)
C2—C3	1.547 (3)	C10—C11	1.384 (3)
C2—H2	0.9800	C10—H10	0.9300
C3—O3	1.443 (2)	C11—C12	1.382 (4)
C3—C4	1.503 (3)	C11—H11	0.9300
C3—H3	0.9800	C12—C13	1.371 (3)
C4—C5	1.345 (3)	C12—O4	1.380 (3)
C4—H4	0.9300	C13—C14	1.374 (3)
C5—C6	1.498 (3)	C13—H13	0.9300
C5—H5	0.9300	C14—H14	0.9300
C6—O3	1.439 (3)	C15—O4	1.360 (3)
C6—C7	1.555 (3)	C15—H15A	0.9600
C6—H6	0.9800	C15—H15B	0.9600
C7—C8	1.491 (3)	C15—H15C	0.9600
C7—H7	0.9800	O1—H1A	0.89 (3)
O1—C1—N1	111.12 (16)	C6—C7—H7	112.5
O1—C1—C2	115.18 (16)	O2—C8—N1	124.7 (2)
N1—C1—C2	104.49 (16)	O2—C8—C7	125.3 (2)
O1—C1—H1	108.6	N1—C8—C7	110.02 (17)
N1—C1—H1	108.6	C10—C9—C14	118.8 (2)
C2—C1—H1	108.6	C10—C9—N1	121.1 (2)
C1—C2—C7	106.36 (16)	C14—C9—N1	120.0 (2)
C1—C2—C3	113.74 (16)	C9—C10—C11	120.9 (2)
C7—C2—C3	100.55 (16)	C9—C10—H10	119.5
C1—C2—H2	111.8	C11—C10—H10	119.5
C7—C2—H2	111.8	C12—C11—C10	119.7 (2)
C3—C2—H2	111.8	C12—C11—H11	120.1
O3—C3—C4	102.03 (18)	C10—C11—H11	120.1
O3—C3—C2	101.04 (16)	C13—C12—O4	115.8 (2)
C4—C3—C2	107.33 (17)	C13—C12—C11	119.4 (2)
O3—C3—H3	114.9	O4—C12—C11	124.8 (2)
C4—C3—H3	114.9	C12—C13—C14	120.7 (2)
C2—C3—H3	114.9	C12—C13—H13	119.6
C5—C4—C3	105.4 (2)	C14—C13—H13	119.6
C5—C4—H4	127.3	C13—C14—C9	120.3 (2)
C3—C4—H4	127.3	C13—C14—H14	119.8
C4—C5—C6	105.1 (2)	C9—C14—H14	119.8
C4—C5—H5	127.5	O4—C15—H15A	109.5
C6—C5—H5	127.5	O4—C15—H15B	109.5
O3—C6—C5	102.27 (18)	H15A—C15—H15B	109.5
O3—C6—C7	100.44 (17)	O4—C15—H15C	109.5
C5—C6—C7	107.15 (17)	H15A—C15—H15C	109.5
O3—C6—H6	115.1	H15B—C15—H15C	109.5
C5—C6—H6	115.1	C8—N1—C9	124.31 (17)
C7—C6—H6	115.1	C8—N1—C1	113.88 (17)
C8—C7—C2	105.22 (17)	C9—N1—C1	121.72 (17)
C8—C7—C6	112.09 (17)	C1—O1—H1A	108.2 (19)
C2—C7—C6	101.45 (16)	C6—O3—C3	95.59 (15)
C8—C7—H7	112.5	C15—O4—C12	118.3 (2)
C2—C7—H7	112.5
O1—C1—C2—C7	121.43 (18)	C9—C10—C11—C12	−1.0 (3)
N1—C1—C2—C7	−0.76 (19)	C10—C11—C12—C13	−0.4 (4)
O1—C1—C2—C3	−128.85 (18)	C10—C11—C12—O4	178.2 (2)
N1—C1—C2—C3	108.96 (17)	O4—C12—C13—C14	−178.1 (2)
C1—C2—C3—O3	−76.44 (19)	C11—C12—C13—C14	0.6 (4)
C7—C2—C3—O3	36.82 (19)	C12—C13—C14—C9	0.4 (4)
C1—C2—C3—C4	177.10 (17)	C10—C9—C14—C13	−1.6 (3)
C7—C2—C3—C4	−69.6 (2)	N1—C9—C14—C13	178.4 (2)
O3—C3—C4—C5	−31.8 (2)	O2—C8—N1—C9	−0.6 (3)
C2—C3—C4—C5	74.0 (2)	C7—C8—N1—C9	177.79 (17)
C3—C4—C5—C6	−0.7 (2)	O2—C8—N1—C1	−177.26 (19)
C4—C5—C6—O3	33.1 (2)	C7—C8—N1—C1	1.1 (2)
C4—C5—C6—C7	−72.1 (2)	C10—C9—N1—C8	41.8 (3)
C1—C2—C7—C8	1.4 (2)	C14—C9—N1—C8	−138.2 (2)
C3—C2—C7—C8	−117.42 (17)	C10—C9—N1—C1	−141.7 (2)
C1—C2—C7—C6	118.28 (17)	C14—C9—N1—C1	38.2 (3)
C3—C2—C7—C6	−0.5 (2)	O1—C1—N1—C8	−125.01 (19)
O3—C6—C7—C8	75.8 (2)	C2—C1—N1—C8	−0.2 (2)
C5—C6—C7—C8	−177.73 (18)	O1—C1—N1—C9	58.2 (2)
O3—C6—C7—C2	−36.0 (2)	C2—C1—N1—C9	−176.96 (16)
C5—C6—C7—C2	70.5 (2)	C5—C6—O3—C3	−50.66 (19)
C2—C7—C8—O2	176.83 (18)	C7—C6—O3—C3	59.65 (18)
C6—C7—C8—O2	67.4 (3)	C4—C3—O3—C6	50.03 (19)
C2—C7—C8—N1	−1.5 (2)	C2—C3—O3—C6	−60.58 (18)
C6—C7—C8—N1	−110.95 (19)	C13—C12—O4—C15	−176.8 (3)
C14—C9—C10—C11	1.9 (3)	C11—C12—O4—C15	4.6 (4)
N1—C9—C10—C11	−178.1 (2)