2,3-Dihydro-3,3-dimethylspiro[1H-4-oxanthracene-5,2'-oxiran]-10(5H)-one

The central six-membered ring in the title compound, C₁₆H₁₆O₃, is almost planar (and almost coplanar with the aromatic ring), despite one of its C atoms being formally sp³ hybridized. The planarity is a consequence of the C atom at the centre of the spiro­cyclic system also being part of the three-membered epoxide ring. The mol­ecules are linked by [pi]-­[pi] and C-H...[pi] interactions.

S1. Comment

α-Lapachone, (I), a 1,4-naphthoquinone, and its 1,2-isomer, β-lapachone, (II), are present as minor components of the lapacho tree (Tabebuia avellanedae Lorentz ex. Griseb; Carvalho et al., 1988). Both have important biological activities. Compound (I), for example, is an irreversible inhibitor of topoisomerase II (Krishnan & Bastow, 2000) and has a number of useful pharmacological properties, including acting as a bacteriocide, fungicide and trypanocide. Compound (III) Should this be (II)? has been intensively investigated pharmacologically, e.g. in cancer chemotherapy (Huang & Pardee, 1999) and in interactions with both topoisomerase I (Li et al., 1993) and topomerase II Should this be topoisomerase II? (Frydman et al., 1997). Lapachol, (III), an open-chain isomer of (I), is also biologically active (dos Santos et al., 2001; Austin, 1974; Pinto et al., 1977). Bioactivation of (III) can lead to DNA scission by NADPH-cytochrome P450 reductase (Kumagai et al., 1997; Molina Portela et al., 1996).

Modification of the redox centre of a naphthoquinone can result in a dramatic change in the biological activity. For example, Pinto et al. (1977) demonstrated that transformations of the o-quinone moieties of lapachones resulted in significant changes in trypanocidal activity. Despite the known pharmacological activities of (I), and the interest in related molecules, few procedures for the selective modification of the redox centre have been described to date. As part of our studies in this area, we have investigated the reaction of (I) with diazomethane. This reaction regiospecifically produced the title monoepoxide, (IV). \sch

The structure of (IV) is shown in Fig. 1. From the determination of a centrosymmetric space group, both enantiomers of (IV) are present in the crystal, the chiral centre being C12. Ring B is only slightly distorted from planarity, as shown by the puckering parameters (Cremer & Pople, 1975) Q = 0.0852 (14) Å and ϕ = 51.4 (10)°. This is despite the presence of the formally sp³-hybridized ring atom, C12. As well as being in the six-membered B ring, atom C12 is also part of the three-membered epoxide ring. The near 60° constraint of angles within the three-membered ring results in an opening up of the other angles at C12, including that within the six-membered ring, to near trigonal angles. The C11—C12—C13 bond angle of 116.57 (11)° is indeed very similar in value to the other internal bond angles in ring B, all of which reflect the sp² hybridization of the ring C atoms. Aromatic ring A, as expected, is planar. The maximum deviation [-0.0981 (14) Å] of atoms from the best plane through rings A and B is exhibited by atom C12. Ring C has a half-chair conformation, with puckering parameters of Q = 0.4502 (19) Å and ϕ = 283.5 (3)°.

Intermolecular interactions in (IV) take the form of π···π and C—H···π interactions; there are no C—H···O hydrogen bonds present. Intermolecular interactions in two polymorphs of compound (III) were reported to include O—H···O hydrogen bonding as well as π···π interactions (Larsen et al., 1992). In two polymorphs of the enol, (III), the intermolecular interactions include O—H···O hydrogen bonding as well as π···π interactions (Larsen et al., 1992).

Molecules of (IV) at (x,y,z) and (2 - x, 1 - y, -z) form π···π stacking interactions involving the A and B rings. The B rings in the two molecules are parallel, with an interplanar spacing of 3.54 Å; with a distance between the ring centroids of 4.05 Å, the offset of the centroids is 1.98 Å. The angle between the planes of ring A at (x,y,z) and ring Bⁱ is 5.39°, with a distance between the ring centroids of 3.74 Å [symmetry code: (i) 2 - x, 1 - y, -z]. The perpendicular distances of the centroids, Cg(A) and Cg(B), from the symmetry-related centroids, Cg(B)ⁱ and Cg(A)ⁱ, are 3.66 and 3.58 Å, respectively, with the interactions forming dimers centred on (1,1/2,0). These are shown in Fig. 2. Rings A and Aⁱ are necessarily parallel, with an interplanar separation of 3.49 Å. Here, however, the distance between the ring centroids is 4.86 Å, so that the offset of the centroids is too long for interaction, at 3.39 Å.

The C—H···π interactions involve methyl H atoms on ring C in molecules at (x,y,z) and the centroid of ring B of molecules at (3/2 - x, 1/2 + y, 1/2 - z), with parameters for C15—H15C···Cg(B) of H···Cg 3.32 Å, C—H···Cg 139.4° and C···Cg 4.093 (3) Å, and for C16—H16A···Cg(B) of H···Cg 3.04 Å, C—H···Cg 146.4° and C···Cg 3.879 (2) Å.

As far as we are aware, (IV) is the first spiro-oxiran derivative of a p-quinone to be reported to date. The regiospecificity of the reaction between diazomethane and (I) clearly shows that the enhanced electrophilic character of the carbonyl C12 atom compared with that of atom C5 far outweighs the greater steric hindrance at the C12—O5 Please clarify - there is no atom O5. Should it be O2? carbonyl group resulting from the neighbouring methyl groups in ring C.

S2. Experimental

A solution of diazomethane (1.2 equivalents) in diethyl ether was added to solid α-lapachone, (I). After 48 h at 277 K, the reaction mixture was rotary evaporated, column chromatographed on silica gel and recrystallized from acetone. The yield of (IV) was 95% (m.p. 391–393 K). Spectroscopic analysis: ¹H NMR (300 MHz, CDCl₃, δ, p.p.m.): 1.36 (3H, s), 1.37 (3H, s), 1.76 (1H, ddd, J = 2.4, 6.6, 7.2 Hz), 1.83 (1H, ddd, J = 2.4, 6.6, 7.5 Hz), 2.39 (1H, ddd, J = 2.1, 6.6, 7.5 Hz), 2.59 (1H, ddd, J = 2.1, 6.3, 7.2 Hz), 3.29 (1H, d, J = 6.9 Hz), 3.65 (1H, d, J = 6.9 Hz), 7.23 (1H, dd, J = 1.5, 7.5 Hz), 7.46 (1H, dd, J = 1.2, 7.5 Hz), 7.54 (1H, dd, J = 1.2, 7.5 Hz), 8.19 (1H, dd, J = 1.5, 7.5 Hz); ¹³C NMR (75 MHz, CDCl₃, δ, p.p.m.): 15.9 (CH₂), 25.7 (CH₃), 31.2 (CH₂), 51.3 (C), 56.8 (CH₂), 77.3 (C), 113.8 (C), 121.9 (CH), 125.7 (CH), 127.8 (CH), 131.4 (CH), 131.9, 136.4 (C), 163.2 (C), 182.9 (C); IR (cm^-1): 3063 (C—H, epoxide), 2928–2983 (C—H), 1621 (C═O), 1575, 1149 (C—O); MS (m/z; low resolution): 200 (100%), 256 (38%), 115 (6%), 223 (5%), 172 (4%); MS (high resolution): M⁺ 256.10107 (C₁₆H₁₆O₃).

S3. Refinement

Compound (IV) is monoclinic; space group P2₁/n was uniquely assigned from the systematic absences. All H atoms were treated as riding atoms, with C—H distances of 0.93, 0.97 and 0.96 Å for phenyl, methylene and methyl H, respectively. Conformational and hydrogen-bonding analyses were performed using PLATON (Spek, 2002).

Computing details

Data collection: SMART (Bruker, 1998); cell refinement: SAINT (Bruker, 2000); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEX in OSCAIL (McArdle, 1994, 2000) and ORTEPIII for Windows (Farrugia, 1997); software used to prepare material for publication: SHELXL97.

Figures

	Fig. 1. A view of the molecule of (IV), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level and H atoms are shown as small spheres of arbitrary radii.
	Fig. 2. The molecules of (IV) within the unit cell. The π···π interactions between centroids are shown as dashed lines. H atoms have been omitted for clarity.

2,3-Dihydro-3,3-dimethylspiro[1H-4-oxanthracene-5,2'-oxiran]-10(5H)-one

Crystal data

C16H16O3	F(000) = 544
Mr = 256.29	Dx = 1.316 Mg m^−3
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2yn	Cell parameters from 4478 reflections
a = 12.2764 (13) Å	θ = 3.4–32.3°
b = 7.8543 (9) Å	µ = 0.09 mm^−1
c = 13.6935 (15) Å	T = 292 K
β = 101.666 (2)°	Block, colourless
V = 1293.1 (2) Å^3	0.5 × 0.4 × 0.4 mm
Z = 4

Data collection

Bruker SMART 1000 CCD area-detector diffractometer	4627 independent reflections
Radiation source: fine-focus sealed tube	2879 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.040
ϕ and ω scans	θmax = 32.6°, θmin = 3.0°
Absorption correction: multi-scan (SADABS; Bruker, 2000)	h = −18→9
Tmin = 0.826, Tmax = 0.928	k = −11→11
12411 measured reflections	l = −20→19

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)] = 0.059	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.187	H-atom parameters constrained
S = 1.01	w = 1/[σ^2(Fo^2) + (0.0895P)^2 + 0.2537P] where P = (Fo^2 + 2Fc^2)/3
4627 reflections	(Δ/σ)max < 0.001
174 parameters	Δρmax = 0.39 e Å^−3
0 restraints	Δρmin = −0.23 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	0.91113 (14)	0.7150 (2)	0.32964 (12)	0.0511 (4)
C2	1.02101 (15)	0.6216 (3)	0.34855 (13)	0.0589 (5)
H2A	1.0752	0.6889	0.3228	0.071*
H2B	1.0475	0.6091	0.4199	0.071*
C3	1.01245 (15)	0.4477 (2)	0.30048 (12)	0.0561 (4)
H3A	1.0864	0.4029	0.3019	0.067*
H3B	0.9742	0.3704	0.3374	0.067*
C4	0.95008 (11)	0.45991 (18)	0.19482 (10)	0.0385 (3)
C5	0.96331 (11)	0.32671 (18)	0.12563 (10)	0.0374 (3)
C6	0.89837 (10)	0.33837 (16)	0.02182 (10)	0.0330 (3)
C7	0.90309 (12)	0.20535 (17)	−0.04362 (11)	0.0417 (3)
H7	0.9502	0.1137	−0.0233	0.050*
C8	0.83876 (15)	0.2076 (2)	−0.13830 (12)	0.0512 (4)
H8	0.8432	0.1187	−0.1822	0.061*
C9	0.76805 (15)	0.3416 (2)	−0.16782 (12)	0.0546 (4)
H9	0.7226	0.3414	−0.2310	0.065*
C10	0.76406 (13)	0.4762 (2)	−0.10435 (11)	0.0472 (4)
H10	0.7170	0.5677	−0.1254	0.057*
C11	0.83007 (10)	0.47622 (17)	−0.00882 (10)	0.0344 (3)
C12	0.82705 (10)	0.61994 (17)	0.05959 (10)	0.0349 (3)
C13	0.88514 (11)	0.59521 (17)	0.16450 (10)	0.0354 (3)
O1	0.86845 (10)	0.72601 (14)	0.22208 (8)	0.0487 (3)
O2	0.72247 (9)	0.70902 (14)	0.04658 (9)	0.0485 (3)
C14	0.81423 (14)	0.79552 (19)	0.02145 (13)	0.0491 (4)
H14A	0.8483	0.8862	0.0653	0.059*
H14B	0.8139	0.8135	−0.0487	0.059*
O3	1.02461 (10)	0.20459 (16)	0.15111 (9)	0.0580 (3)
C15	0.9240 (2)	0.8984 (3)	0.36169 (19)	0.0861 (7)
H15A	0.9779	0.9525	0.3301	0.129*
H15B	0.9484	0.9041	0.4328	0.129*
H15C	0.8538	0.9556	0.3426	0.129*
C16	0.82301 (19)	0.6245 (3)	0.37286 (17)	0.0761 (6)
H16A	0.7538	0.6846	0.3546	0.114*
H16B	0.8452	0.6210	0.4442	0.114*
H16C	0.8141	0.5105	0.3472	0.114*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0564 (9)	0.0538 (9)	0.0430 (8)	0.0003 (7)	0.0100 (6)	−0.0115 (7)
C2	0.0527 (9)	0.0731 (12)	0.0464 (9)	0.0015 (9)	−0.0009 (7)	−0.0129 (8)
C3	0.0583 (9)	0.0623 (10)	0.0416 (8)	0.0191 (8)	−0.0043 (7)	−0.0034 (7)
C4	0.0372 (6)	0.0395 (7)	0.0368 (7)	0.0057 (5)	0.0029 (5)	−0.0001 (5)
C5	0.0373 (6)	0.0338 (6)	0.0398 (7)	0.0067 (5)	0.0049 (5)	0.0040 (5)
C6	0.0348 (5)	0.0269 (5)	0.0375 (6)	−0.0004 (4)	0.0074 (5)	0.0029 (4)
C7	0.0493 (7)	0.0274 (6)	0.0487 (8)	0.0000 (5)	0.0104 (6)	0.0005 (5)
C8	0.0679 (10)	0.0365 (7)	0.0475 (8)	−0.0087 (7)	0.0078 (7)	−0.0073 (6)
C9	0.0648 (10)	0.0516 (9)	0.0409 (8)	−0.0069 (8)	−0.0046 (7)	−0.0007 (7)
C10	0.0503 (7)	0.0425 (8)	0.0439 (8)	0.0045 (6)	−0.0022 (6)	0.0052 (6)
C11	0.0349 (5)	0.0303 (6)	0.0372 (6)	−0.0003 (5)	0.0057 (5)	0.0039 (5)
C12	0.0349 (5)	0.0295 (6)	0.0406 (7)	0.0055 (5)	0.0081 (5)	0.0050 (5)
C13	0.0358 (5)	0.0332 (6)	0.0376 (6)	0.0017 (5)	0.0085 (5)	−0.0015 (5)
O1	0.0584 (6)	0.0420 (6)	0.0451 (6)	0.0113 (5)	0.0092 (5)	−0.0072 (4)
O2	0.0424 (5)	0.0432 (6)	0.0597 (7)	0.0148 (4)	0.0095 (4)	0.0076 (5)
C14	0.0605 (9)	0.0328 (7)	0.0563 (9)	0.0089 (6)	0.0170 (7)	0.0084 (6)
O3	0.0663 (7)	0.0483 (7)	0.0540 (7)	0.0275 (6)	−0.0008 (5)	0.0030 (5)
C15	0.1047 (18)	0.0669 (14)	0.0820 (15)	0.0018 (13)	0.0072 (13)	−0.0355 (12)
C16	0.0726 (13)	0.0943 (17)	0.0683 (13)	0.0036 (12)	0.0302 (10)	0.0011 (12)

Geometric parameters (Å, º)

O1—C1	1.4627 (19)	C6—C7	1.3852 (19)
O2—C12	1.4412 (15)	C7—C8	1.375 (2)
O2—C14	1.416 (2)	C7—H7	0.9300
O3—C5	1.2255 (16)	C8—C9	1.372 (2)
C4—C13	1.3430 (18)	C8—H8	0.9300
C4—C5	1.443 (2)	C9—C10	1.376 (2)
C5—C6	1.4854 (18)	C9—H9	0.9300
C6—C11	1.3817 (17)	C10—C11	1.3926 (18)
C11—C12	1.4721 (19)	C10—H10	0.9300
C12—C13	1.4818 (18)	C12—C14	1.4717 (19)
C1—C15	1.505 (3)	C13—O1	1.3358 (16)
C1—C2	1.511 (2)	C14—H14A	0.9700
C1—C16	1.512 (3)	C14—H14B	0.9700
C2—C3	1.510 (3)	C15—H15A	0.9600
C2—H2A	0.9700	C15—H15B	0.9600
C2—H2B	0.9700	C15—H15C	0.9600
C3—C4	1.4969 (19)	C16—H16A	0.9600
C3—H3A	0.9700	C16—H16B	0.9600
C3—H3B	0.9700	C16—H16C	0.9600
C11—C12—C13	116.57 (11)	C8—C7—H7	119.7
O2—C12—C11	115.47 (11)	C6—C7—H7	119.7
C14—C12—C11	120.49 (12)	C9—C8—C7	119.75 (14)
C14—C12—C13	117.57 (12)	C9—C8—H8	120.1
O2—C12—C13	115.18 (11)	C7—C8—H8	120.1
C14—O2—C12	61.99 (9)	C8—C9—C10	120.30 (14)
O2—C12—C14	58.17 (9)	C8—C9—H9	119.9
O2—C14—C12	59.83 (9)	C10—C9—H9	119.9
O1—C1—C15	103.42 (16)	C9—C10—C11	120.33 (14)
O1—C1—C2	109.08 (13)	C9—C10—H10	119.8
C15—C1—C2	112.18 (17)	C11—C10—H10	119.8
O1—C1—C16	106.45 (14)	C6—C11—C10	119.17 (13)
C15—C1—C16	112.15 (18)	C6—C11—C12	119.97 (11)
C2—C1—C16	112.91 (18)	C10—C11—C12	120.86 (12)
C3—C2—C1	112.54 (14)	O1—C13—C4	125.34 (12)
C3—C2—H2A	109.1	O1—C13—C12	111.73 (11)
C1—C2—H2A	109.1	C4—C13—C12	122.87 (12)
C3—C2—H2B	109.1	C13—O1—C1	118.84 (12)
C1—C2—H2B	109.1	O2—C14—H14A	117.8
H2A—C2—H2B	107.8	C12—C14—H14A	117.8
C4—C3—C2	109.89 (14)	O2—C14—H14B	117.8
C4—C3—H3A	109.7	C12—C14—H14B	117.8
C2—C3—H3A	109.7	H14A—C14—H14B	114.9
C4—C3—H3B	109.7	C1—C15—H15A	109.5
C2—C3—H3B	109.7	C1—C15—H15B	109.5
H3A—C3—H3B	108.2	H15A—C15—H15B	109.5
C13—C4—C5	120.63 (12)	C1—C15—H15C	109.5
C13—C4—C3	120.35 (13)	H15A—C15—H15C	109.5
C5—C4—C3	119.00 (12)	H15B—C15—H15C	109.5
O3—C5—C4	121.66 (13)	C1—C16—H16A	109.5
O3—C5—C6	120.04 (13)	C1—C16—H16B	109.5
C4—C5—C6	118.29 (11)	H16A—C16—H16B	109.5
C11—C6—C7	119.79 (12)	C1—C16—H16C	109.5
C11—C6—C5	120.94 (12)	H16A—C16—H16C	109.5
C7—C6—C5	119.21 (12)	H16B—C16—H16C	109.5
C8—C7—C6	120.60 (13)