Ethyl 5-methyl-3-[11-(pyridin-2-yl)-6,11-dihydro-6,11-epoxydibenzo[b,e]oxepin-6-yl]isoxazole-4-carboxylate: a bicyclic acetal from the rearrangement of an anthracenyl isoxazole

The title compound, a rearrangement product of an o-pyridinyl anthracenyl isoxazole ester, features a bicyclic acetal structure, which has two extended almost co-planar ring systems, which subtend a fold angle of 102.17 (5)°. In the crystal, the molecules are closely knitted together through C—H⋯N and C—H⋯O hydrogen bonds and form chains of alternating enantiomers propagating along the c-axis direction.


Chemical context
We have reported on 3-aryl isoxazole amides (AIMs) with antitumor activity (Han et al., 2009;Weaver et al., 2015) and recently described 10-substituted anthracenes with N-heterocyclic substituents in this series, which possessed robust antitumor activity against both breast and brain tumor cell lines (Weaver et al., 2020). In the course of that study, we attempted to obtain crystals of the 10-o-pyridyl example II by slow evaporation (see Fig. 1). After numerous attempts, suitable crystals were obtained but were found to have undergone oxygen addition and rearrangement to the title compound, C 26 H 20 N 2 O 5 , I. This is unprecedented in this series of compounds.
In the case of the o-pyridyl ester, slow evaporation from solution was observed to produce a bicyclic acetal (BA). This requires the formation of a dioxygen adduct commonly found in the anthracene literature (Klaper et al., 2016), as shown in Fig. 1. This dioxygen adduct III is most often observed as a [4 + 2] cycloadduct with singlet oxygen (Lauer et al., 2011), and in some cases where a donor-acceptor pair sensitizes the formation of singlet oxygen. It should be noted, however, that the endo peroxide can be formed from the ground-state diradical oxygen in a one-electron process. ISSN 2056-9890 The bicyclic acetal (BA) I can be formed directly via a Criegee-like rearrangement through intermediate IV, or alternatively stepwise via the intermediacy of one electron reorganization to an intermediate diepoxide V (Filatov et al., 2017). Of the ten previous crystal structures of anthryl isoxazoles published by our group (Mosher et al., 1996;Han et al., 2002Han et al., , 2003Li et al., 2006Li et al., , 2008Li et al., 2013;Duncan et al., 2014;Weaver et al., 2015), and the three N-heterocyclic structures solved and disclosed (Weaver et al., 2020), this is the first example we have observed of this rearrangement. Given the observation of this rearrangement it is advisable that the o-pyridyl AIM (II) be stored under an argon atmosphere at low temperature (233 K or below).
Conditions within tumors are notoriously anoxic. As an example, the transition to the Warberg phenotype (Vander Heiden et al., 2009) is heavily influenced by the transcription factor hypoxia inducing factor (HIF). Therefore, the physiological relevance and therapeutic practicality of this process appears questionable, particularly considering that the endo peroxide (III) or the diepoxide (V) would not be expected to exert significant selectivity. Therefore, the probability of a useful therapeutic index would appear low. However, the prospects for exploiting this tactic will be considered, even if they constitute only negative controls, in our ongoing studies of antitumor theranostics, and will be reported in due course.

Structural commentary
The title compound crystallizes as a racemate in the monoclinic space group, P2 1 /c, with one independent molecule in the asymmetric unit (Fig. 2). In the arbitrarily chosen asymmetric molecule, atoms C7 and C14 both have R configura-tions. The insertion of two oxygen atoms in the central ring of anthracene forms a bicyclic system with one oxygen atom (O1) in the middle shared by both dioxane and furan rings. The remainder of the dioxane and furan ring atoms are co-planar with the C1-C6 and C8-C13 benzene rings on either side, respectively. The pyridine group is attached at the ortho position to one of the shared carbon atoms on the bicyclic system, while the isoxazole ester is attached to the other shared carbon atom. The overall effect of the bonding gives the whole molecule a dragon-like appearance.
The planarity of each wing is indicated by the r.m.s.d. of 0.028 Å for both planes formed by C1-C7/C14/O2 and C7-C14. These two wings are flapping downwards with a fold angle between them of 102.17 (5) . The pyridine group is the head of the dragon with the nitrogen atom being exo to the oxygen atom (O1) in the backbone. A potential hydrogen bond between C23-H23 and O1 may contribute to the small torsion angle of 2.2 (3) for O1-C7-C22-C23. Both the nitrogen and oxygen atoms in the isoxazole ring are exo to the oxygen atoms (O1 and O2) in the dioxane ring, resulting in the ethyl ester tail swinging to the dioxane side and coming to rest between the two oxygen atoms. There is ainteraction between the tip of the tail (methyl group) and the benzene ring, which is also reflected by the upfield shift of CH 3 protons in the NMR spectrum.

Supramolecular features
In the crystal, chains of alternating enantiomers are formed running along the c-axis direction through the intermolecular hydrogen bonds C23-H23Á Á ÁN1 i , C12-H12Á Á ÁO1 ii and C18-H18BÁ Á ÁO4 ii (Table 1    knitted, which may contribute to the formation of needleshaped crystals.

Hirshfeld surface analysis
The intermolecular interactions were quantified using Hirshfeld surface analysis (Spackman & Jayatilaka, 2009) and the associated two-dimensional fingerprint plots (McKinnon et al., 2007). The calculations and visualization were performed using CrystalExplorer17 (Turner et al., 2017). The Hirshfeld surface of the title compound is mapped over d norm in a fixed color scale of À0.1374 (red) to +1.3125 (blue) arbitrary units ( Fig. 4), where the red spots indicate the intermolecular contacts shorter than the van der Waals separations. The delineated two-dimensional fingerprint plots are shown in Hirshfeld surface of I mapped over d norm . Short contacts between carbonyl C19 O3 and isoxazole O3-C17 are shown in dashed red lines. Intermolecular hydrogen bonds O1Á Á ÁH12 and N1Á Á ÁH23 are shown as dashed green lines.

Figure 3
The packing of I. A closely knitted chain of alternating enantiomers is formed through several intermolecular hydrogen bonds. For clarity, H atoms not participating in intermolecular bonds are omitted. Atoms participating in intermolecular hydrogen bonds are labeled once.

Database survey
A search for the 6,11-dihydro-6,11-epoxydibenzo[b,e]oxepin fragment in the Cambridge Structural Database (CSD version 5.40, August 2019 update; Groom et al., 2016) resulted in five hits, namely refcodes LIPZEP (Walker et al., 1999), NEJLOG (Filatov et al., 2017), VAZDEI, VAZDIM (Ando et al., 2017), and WOPGAM (Ando et al., 2019). These five structures, despite their different substitution groups and positions, all exhibit a similar a structural configuration, that with shared oxygen atom pointing up, and the remainder of the five-and seven-membered rings on the bicyclic system are co-planar to their respective benzene rings.

Synthesis and crystallization
The title compound was synthesized from the o-pyridylanthracenyl isoxazole ester (II) (Weaver et al., 2020

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. All hydrogen atoms were found in difference-Fourier maps and their positions were freely refined with the constraint U iso (H) = 1.2 or 1.5U eq (parent). Seven reflections were omitted because of poor agreement between the observed and calculated intensities. Facility under contract No. DE-AC02-05CH11231. CL is grateful for both Dr Krause's guidance in processing synchrotron data and her helpful comments that improved the manuscript.    program(s) used to solve structure: SHELXS (Sheldrick, 2008); program(s) used to refine structure: SHELXL (Sheldrick, 2015); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: publCIF (Westrip, 2010).

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.