research communications
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
aDepartment of Biomedical & Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA, and bDepartment of Chemistry, Ithaca College, 953 Danby Road, Ithaca, NY 14850, USA
*Correspondence e-mail: nicholas.natale@mso.umt.edu
The title compound, C26H20N2O5, is a rearrangement product of an o-pyridinyl anthracenyl isoxazole ester. It 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.
CCDC reference: 2041149
1. Chemical context
We have reported on 3-aryl isoxazole 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, C26H20N2O5, I. This is unprecedented in this series of compounds.
(AIMs) with antitumor activity (HanIn 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.
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., 2002, 2003; Li et al., 2006, 2008; Li 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.
2. Structural commentary
The title compound crystallizes as a racemate in the monoclinic P21/c, with one independent molecule in the (Fig. 2). In the arbitrarily chosen asymmetric molecule, atoms C7 and C14 both have R configurations. 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 a σ–π interaction between the tip of the tail (methyl group) and the benzene ring, which is also reflected by the upfield shift of CH3 protons in the NMR spectrum.
3. Supramolecular features
In the crystal, chains of alternating enantiomers are formed running along the c-axis direction through the intermolecular hydrogen bonds C23—H23⋯N1i, C12—H12⋯O1ii and C18—H18B⋯O4ii (Table 1, Fig. 3). This chain is highly knitted, which may contribute to the formation of needle-shaped crystals.
4. 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 dnorm in a fixed color scale of −0.1374 (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 Fig. 5, and demonstrate that the main contribution to the overall Hirshfeld surface area arises from H⋯H contacts (50.5%, Fig. 5a). The C⋯H/H⋯C contacts (24.7%, Fig. 5b), which indicate C—H⋯π interactions, are identifiable from the Hirshfeld surface mapped over the shape-index property (Fig. 6). Conventional hydrogen-bonding interactions, H⋯O/O⋯H and N⋯H/H⋯N, only comprise 12.9% and 4.2% of the intermolecular interactions, respectively (Fig. 5b and 5c).
5. 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.
6. Synthesis and crystallization
The title compound was synthesized from the o-pyridyl-anthracenyl isoxazole ester (II) (Weaver et al., 2020). Colorless needles were obtained by slow evaporation in the presence of atmospheric oxygen over a period of several months. 1H NMR (CDCl3) δppm 8.895 (d, 1H, J = 5Hz); 8.13 (dd, 1H, J = 6 Hz); 7.8 (d, 2H, J = 4 Hz); 7.57 (dt, 1H); 7.34 (m, 4H); 7.16 (m, 1H); 6.85 (d, 1H, 8 Hz); 6.79 (t, 1H, J = 8 Hz); 3.975 (q, 1H, J = 7 Hz); 3.845 (q, 1H, J = 7 Hz); 2.79 (s, 3H); 0.63 (t, 3H, J = 7 Hz). 13C NMR (CDCl3) δppm 176.69, 161.73 158.05, 156.86, 150.24, 148.55, 146.15, 135.98, 136.88, 129.35, 128.44, 128.17, 123.27, 123.09, 122.16, 121.46, 121.35, 120.46, 117.01, 60.91, 13.14. 13.08. The proton–proton correlation is provided in the supporting information. Positive electrospray ionization (ESI) calc. for [C26H20N2O3+H]+ 441.44, observed m/z 441.2 ([M + H]+, 100% rel. intensity).
7. Refinement
Crystal data, data collection and structure . All hydrogen atoms were found in difference-Fourier maps and their positions were freely refined with the constraint Uiso(H) = 1.2 or 1.5Ueq(parent). Seven reflections were omitted because of poor agreement between the observed and calculated intensities.
details are summarized in Table 2Supporting information
CCDC reference: 2041149
https://doi.org/10.1107/S2056989020014358/hb7949sup1.cif
contains datablock I. DOI:Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989020014358/hb7949Isup2.hkl
Proton-Proton COSY of the title compound. DOI: https://doi.org/10.1107/S2056989020014358/hb7949sup3.pdf
Supporting information file. DOI: https://doi.org/10.1107/S2056989020014358/hb7949Isup4.cml
Data collection: APEX3 (Bruker, 2016); cell
SAINT (Bruker, 2016); data reduction: SAINT (Bruker, 2016); 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).C26H20N2O5 | F(000) = 920 |
Mr = 440.44 | Dx = 1.379 Mg m−3 |
Monoclinic, P21/c | Synchrotron radiation, λ = 0.7288 Å |
a = 19.0586 (7) Å | Cell parameters from 9997 reflections |
b = 13.9627 (5) Å | θ = 2.7–29.0° |
c = 8.1459 (3) Å | µ = 0.10 mm−1 |
β = 101.7800 (11)° | T = 150 K |
V = 2122.05 (13) Å3 | Needle, colourless |
Z = 4 | 0.11 × 0.01 × 0.01 mm |
Bruker PHOTON-II diffractometer | 5275 independent reflections |
Radiation source: synchrotron | 3947 reflections with I > 2σ(I) |
Si-<111> channnel cut crystal monochromator | Rint = 0.067 |
ω–phi scans | θmax = 29.1°, θmin = 1.1° |
Absorption correction: multi-scan (SADABS; Krause et al., 2015) | h = −25→25 |
k = −18→18 | |
71254 measured reflections | l = −10→10 |
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Hydrogen site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.052 | All H-atom parameters refined |
wR(F2) = 0.145 | w = 1/[σ2(Fo2) + (0.0476P)2 + 2.6861P] where P = (Fo2 + 2Fc2)/3 |
S = 1.05 | (Δ/σ)max < 0.001 |
5275 reflections | Δρmax = 0.28 e Å−3 |
378 parameters | Δρmin = −0.27 e Å−3 |
0 restraints |
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. |
x | y | z | Uiso*/Ueq | ||
O1 | 0.24461 (7) | 0.07865 (10) | 0.35674 (16) | 0.0202 (3) | |
O2 | 0.29900 (8) | 0.07367 (10) | 0.64004 (17) | 0.0223 (3) | |
O3 | 0.34820 (8) | 0.35999 (10) | 0.50102 (19) | 0.0261 (3) | |
O4 | 0.47276 (9) | 0.15114 (12) | 0.3200 (2) | 0.0361 (4) | |
O5 | 0.39223 (8) | 0.05030 (11) | 0.3916 (2) | 0.0296 (4) | |
N1 | 0.29207 (9) | 0.29999 (12) | 0.5258 (2) | 0.0238 (4) | |
N2 | 0.09144 (10) | −0.07696 (14) | 0.2123 (2) | 0.0292 (4) | |
C1 | 0.27403 (12) | −0.01948 (14) | 0.6403 (3) | 0.0232 (4) | |
C2 | 0.30636 (13) | −0.07614 (16) | 0.7747 (3) | 0.0287 (5) | |
C3 | 0.28365 (14) | −0.17036 (16) | 0.7839 (3) | 0.0344 (5) | |
C4 | 0.22965 (14) | −0.20738 (16) | 0.6600 (3) | 0.0326 (5) | |
C5 | 0.19750 (13) | −0.14975 (15) | 0.5254 (3) | 0.0266 (5) | |
C6 | 0.21931 (11) | −0.05535 (14) | 0.5141 (2) | 0.0211 (4) | |
C7 | 0.18559 (10) | 0.01676 (13) | 0.3788 (2) | 0.0193 (4) | |
C8 | 0.14033 (11) | 0.08444 (13) | 0.4614 (2) | 0.0193 (4) | |
C9 | 0.06981 (11) | 0.07996 (15) | 0.4768 (3) | 0.0228 (4) | |
C10 | 0.04475 (12) | 0.15003 (16) | 0.5736 (3) | 0.0263 (4) | |
C11 | 0.09066 (12) | 0.22102 (16) | 0.6540 (3) | 0.0272 (5) | |
C12 | 0.16221 (11) | 0.22441 (15) | 0.6391 (2) | 0.0226 (4) | |
C13 | 0.18632 (11) | 0.15600 (14) | 0.5409 (2) | 0.0197 (4) | |
C14 | 0.26003 (11) | 0.13279 (14) | 0.5063 (2) | 0.0201 (4) | |
C15 | 0.31029 (11) | 0.21370 (14) | 0.4879 (2) | 0.0202 (4) | |
C16 | 0.37804 (11) | 0.21339 (15) | 0.4366 (2) | 0.0227 (4) | |
C17 | 0.39812 (12) | 0.30763 (15) | 0.4467 (3) | 0.0249 (4) | |
C18 | 0.46053 (15) | 0.3608 (2) | 0.4110 (4) | 0.0355 (5) | |
C19 | 0.41961 (11) | 0.13631 (16) | 0.3764 (3) | 0.0254 (4) | |
C20 | 0.42398 (14) | −0.02839 (17) | 0.3144 (3) | 0.0330 (5) | |
C21 | 0.38260 (19) | −0.1163 (2) | 0.3364 (5) | 0.0555 (9) | |
C22 | 0.14987 (11) | −0.02307 (14) | 0.2102 (2) | 0.0214 (4) | |
C23 | 0.17449 (13) | −0.00322 (17) | 0.0645 (3) | 0.0285 (5) | |
C24 | 0.13755 (14) | −0.04157 (19) | −0.0852 (3) | 0.0344 (5) | |
C25 | 0.07809 (14) | −0.09848 (18) | −0.0845 (3) | 0.0347 (5) | |
C26 | 0.05705 (14) | −0.11353 (18) | 0.0655 (3) | 0.0343 (5) | |
H5 | 0.1576 (13) | −0.1717 (17) | 0.441 (3) | 0.023 (6)* | |
H4 | 0.2093 (14) | −0.276 (2) | 0.662 (3) | 0.037 (7)* | |
H24 | 0.1525 (15) | −0.028 (2) | −0.187 (4) | 0.038 (7)* | |
H3 | 0.3064 (15) | −0.214 (2) | 0.884 (4) | 0.042 (8)* | |
H25 | 0.0550 (15) | −0.128 (2) | −0.186 (4) | 0.042 (8)* | |
H23 | 0.2149 (15) | 0.043 (2) | 0.067 (3) | 0.037 (7)* | |
H20A | 0.4748 (15) | −0.0340 (19) | 0.366 (3) | 0.034 (7)* | |
H9 | 0.0375 (14) | 0.0326 (19) | 0.423 (3) | 0.029 (6)* | |
H20B | 0.4242 (18) | −0.013 (2) | 0.194 (4) | 0.060 (9)* | |
H2 | 0.3400 (15) | −0.053 (2) | 0.861 (4) | 0.036 (7)* | |
H10 | −0.0068 (16) | 0.148 (2) | 0.583 (4) | 0.045 (8)* | |
H26 | 0.0124 (16) | −0.152 (2) | 0.070 (3) | 0.043 (8)* | |
H11 | 0.0758 (14) | 0.269 (2) | 0.723 (3) | 0.036 (7)* | |
H12 | 0.1939 (14) | 0.272 (2) | 0.692 (3) | 0.037 (7)* | |
H18A | 0.492 (2) | 0.386 (3) | 0.506 (5) | 0.080 (12)* | |
H21A | 0.332 (2) | −0.108 (2) | 0.279 (4) | 0.062 (10)* | |
H18B | 0.495 (2) | 0.317 (3) | 0.373 (5) | 0.079 (12)* | |
H21B | 0.403 (2) | −0.175 (3) | 0.273 (5) | 0.097 (14)* | |
H18C | 0.451 (2) | 0.395 (3) | 0.322 (6) | 0.095 (15)* | |
H21C | 0.385 (2) | −0.129 (3) | 0.471 (5) | 0.080 (12)* |
U11 | U22 | U33 | U12 | U13 | U23 | |
O1 | 0.0246 (7) | 0.0169 (6) | 0.0200 (6) | −0.0032 (5) | 0.0065 (5) | −0.0011 (5) |
O2 | 0.0264 (7) | 0.0168 (7) | 0.0225 (7) | −0.0009 (6) | 0.0024 (6) | 0.0027 (5) |
O3 | 0.0292 (8) | 0.0186 (7) | 0.0320 (8) | −0.0061 (6) | 0.0096 (6) | −0.0011 (6) |
O4 | 0.0313 (9) | 0.0360 (9) | 0.0452 (10) | −0.0020 (7) | 0.0176 (8) | −0.0050 (8) |
O5 | 0.0284 (8) | 0.0203 (7) | 0.0424 (9) | 0.0007 (6) | 0.0124 (7) | −0.0039 (6) |
N1 | 0.0246 (9) | 0.0199 (8) | 0.0274 (9) | −0.0048 (7) | 0.0065 (7) | 0.0007 (7) |
N2 | 0.0326 (10) | 0.0281 (9) | 0.0279 (9) | −0.0085 (8) | 0.0084 (8) | −0.0047 (7) |
C1 | 0.0294 (11) | 0.0172 (9) | 0.0246 (10) | 0.0018 (8) | 0.0094 (8) | 0.0012 (7) |
C2 | 0.0367 (12) | 0.0226 (10) | 0.0264 (11) | 0.0027 (9) | 0.0053 (9) | 0.0019 (8) |
C3 | 0.0497 (15) | 0.0225 (11) | 0.0317 (12) | 0.0083 (10) | 0.0097 (11) | 0.0078 (9) |
C4 | 0.0482 (14) | 0.0171 (10) | 0.0339 (12) | 0.0009 (10) | 0.0120 (10) | 0.0030 (9) |
C5 | 0.0367 (12) | 0.0173 (10) | 0.0276 (10) | −0.0015 (8) | 0.0110 (9) | −0.0017 (8) |
C6 | 0.0266 (10) | 0.0168 (9) | 0.0218 (9) | 0.0017 (8) | 0.0093 (8) | 0.0006 (7) |
C7 | 0.0226 (10) | 0.0148 (9) | 0.0220 (9) | −0.0017 (7) | 0.0078 (7) | 0.0004 (7) |
C8 | 0.0254 (10) | 0.0138 (8) | 0.0196 (9) | −0.0005 (7) | 0.0067 (7) | 0.0007 (7) |
C9 | 0.0244 (10) | 0.0200 (10) | 0.0246 (10) | −0.0038 (8) | 0.0068 (8) | 0.0001 (8) |
C10 | 0.0250 (11) | 0.0265 (11) | 0.0293 (11) | 0.0000 (8) | 0.0104 (9) | −0.0008 (8) |
C11 | 0.0319 (12) | 0.0235 (10) | 0.0289 (10) | 0.0021 (9) | 0.0122 (9) | −0.0045 (8) |
C12 | 0.0273 (11) | 0.0185 (9) | 0.0219 (9) | −0.0018 (8) | 0.0046 (8) | −0.0029 (7) |
C13 | 0.0231 (10) | 0.0174 (9) | 0.0190 (9) | −0.0011 (7) | 0.0049 (7) | 0.0015 (7) |
C14 | 0.0251 (10) | 0.0167 (9) | 0.0184 (9) | 0.0003 (8) | 0.0040 (7) | 0.0007 (7) |
C15 | 0.0238 (10) | 0.0176 (9) | 0.0188 (9) | −0.0009 (7) | 0.0033 (7) | −0.0001 (7) |
C16 | 0.0245 (10) | 0.0224 (10) | 0.0211 (9) | −0.0012 (8) | 0.0049 (8) | 0.0009 (8) |
C17 | 0.0277 (11) | 0.0232 (10) | 0.0239 (10) | −0.0024 (8) | 0.0057 (8) | 0.0003 (8) |
C18 | 0.0354 (13) | 0.0327 (13) | 0.0409 (14) | −0.0113 (11) | 0.0136 (11) | −0.0006 (11) |
C19 | 0.0249 (11) | 0.0271 (11) | 0.0242 (10) | −0.0006 (8) | 0.0052 (8) | −0.0016 (8) |
C20 | 0.0318 (13) | 0.0261 (11) | 0.0424 (13) | 0.0051 (9) | 0.0106 (10) | −0.0080 (10) |
C21 | 0.055 (2) | 0.0274 (13) | 0.093 (3) | −0.0047 (13) | 0.0343 (19) | −0.0172 (15) |
C22 | 0.0266 (10) | 0.0152 (9) | 0.0230 (9) | 0.0007 (7) | 0.0060 (8) | −0.0010 (7) |
C23 | 0.0332 (12) | 0.0287 (11) | 0.0244 (10) | −0.0029 (9) | 0.0078 (9) | −0.0019 (8) |
C24 | 0.0412 (14) | 0.0411 (14) | 0.0219 (10) | −0.0040 (11) | 0.0089 (10) | −0.0041 (9) |
C25 | 0.0369 (13) | 0.0380 (13) | 0.0270 (11) | −0.0046 (10) | 0.0012 (10) | −0.0094 (10) |
C26 | 0.0344 (13) | 0.0339 (12) | 0.0339 (12) | −0.0100 (10) | 0.0052 (10) | −0.0083 (10) |
O1—C7 | 1.458 (2) | C10—C11 | 1.394 (3) |
O1—C14 | 1.413 (2) | C10—H10 | 1.00 (3) |
O2—C1 | 1.385 (2) | C11—C12 | 1.394 (3) |
O2—C14 | 1.446 (2) | C11—H11 | 0.95 (3) |
O3—N1 | 1.405 (2) | C12—C13 | 1.383 (3) |
O3—C17 | 1.344 (3) | C12—H12 | 0.94 (3) |
O4—C19 | 1.212 (3) | C13—C14 | 1.523 (3) |
O5—C19 | 1.325 (3) | C14—C15 | 1.508 (3) |
O5—C20 | 1.457 (3) | C15—C16 | 1.436 (3) |
N1—C15 | 1.308 (3) | C16—C17 | 1.368 (3) |
N2—C22 | 1.347 (3) | C16—C19 | 1.478 (3) |
N2—C26 | 1.342 (3) | C17—C18 | 1.480 (3) |
C1—C2 | 1.389 (3) | C18—H18A | 0.94 (4) |
C1—C6 | 1.399 (3) | C18—H18B | 0.99 (4) |
C2—C3 | 1.392 (3) | C18—H18C | 0.86 (5) |
C2—H2 | 0.91 (3) | C20—C21 | 1.489 (4) |
C3—C4 | 1.386 (4) | C20—H20A | 0.98 (3) |
C3—H3 | 1.04 (3) | C20—H20B | 1.00 (3) |
C4—C5 | 1.397 (3) | C21—H21A | 1.00 (4) |
C4—H4 | 1.03 (3) | C21—H21B | 1.08 (4) |
C5—C6 | 1.391 (3) | C21—H21C | 1.11 (4) |
C5—H5 | 0.96 (2) | C22—C23 | 1.391 (3) |
C6—C7 | 1.534 (3) | C23—C24 | 1.385 (3) |
C7—C8 | 1.525 (3) | C23—H23 | 1.00 (3) |
C7—C22 | 1.509 (3) | C24—C25 | 1.385 (4) |
C8—C9 | 1.377 (3) | C24—H24 | 0.95 (3) |
C8—C13 | 1.398 (3) | C25—C26 | 1.378 (3) |
C9—C10 | 1.400 (3) | C25—H25 | 0.94 (3) |
C9—H9 | 0.95 (3) | C26—H26 | 1.02 (3) |
C14—O1—C7 | 103.92 (14) | O1—C14—C15 | 109.84 (15) |
C1—O2—C14 | 114.43 (15) | O2—C14—C13 | 109.49 (15) |
C17—O3—N1 | 109.49 (15) | O2—C14—C15 | 105.29 (15) |
C19—O5—C20 | 115.89 (17) | C15—C14—C13 | 119.18 (16) |
C15—N1—O3 | 105.57 (16) | N1—C15—C14 | 117.49 (17) |
C26—N2—C22 | 117.14 (19) | N1—C15—C16 | 111.68 (18) |
O2—C1—C2 | 116.04 (19) | C16—C15—C14 | 130.82 (18) |
O2—C1—C6 | 122.66 (18) | C15—C16—C19 | 132.33 (19) |
C2—C1—C6 | 121.30 (19) | C17—C16—C15 | 103.68 (18) |
C1—C2—C3 | 119.2 (2) | C17—C16—C19 | 123.92 (19) |
C1—C2—H2 | 122.2 (18) | O3—C17—C16 | 109.57 (18) |
C3—C2—H2 | 118.5 (17) | O3—C17—C18 | 116.29 (19) |
C2—C3—H3 | 120.6 (16) | C16—C17—C18 | 134.1 (2) |
C4—C3—C2 | 120.4 (2) | C17—C18—H18A | 115 (2) |
C4—C3—H3 | 119.0 (16) | C17—C18—H18B | 112 (2) |
C3—C4—C5 | 119.9 (2) | C17—C18—H18C | 114 (3) |
C3—C4—H4 | 124.1 (15) | H18A—C18—H18B | 98 (3) |
C5—C4—H4 | 115.9 (15) | H18A—C18—H18C | 118 (4) |
C4—C5—H5 | 122.1 (14) | H18B—C18—H18C | 97 (3) |
C6—C5—C4 | 120.6 (2) | O4—C19—O5 | 124.4 (2) |
C6—C5—H5 | 117.2 (14) | O4—C19—C16 | 123.2 (2) |
C1—C6—C7 | 115.67 (17) | O5—C19—C16 | 112.39 (18) |
C5—C6—C1 | 118.60 (19) | O5—C20—C21 | 107.0 (2) |
C5—C6—C7 | 125.64 (19) | O5—C20—H20A | 109.8 (16) |
O1—C7—C6 | 104.89 (15) | O5—C20—H20B | 110.4 (19) |
O1—C7—C8 | 101.96 (14) | C21—C20—H20A | 112.7 (16) |
O1—C7—C22 | 108.79 (15) | C21—C20—H20B | 113.4 (19) |
C8—C7—C6 | 106.35 (15) | H20A—C20—H20B | 104 (2) |
C22—C7—C6 | 117.20 (16) | C20—C21—H21A | 110 (2) |
C22—C7—C8 | 116.05 (17) | C20—C21—H21B | 109 (2) |
C9—C8—C7 | 131.50 (18) | C20—C21—H21C | 110 (2) |
C9—C8—C13 | 121.45 (18) | H21A—C21—H21B | 106 (3) |
C13—C8—C7 | 106.83 (17) | H21A—C21—H21C | 109 (3) |
C8—C9—C10 | 118.11 (19) | H21B—C21—H21C | 114 (3) |
C8—C9—H9 | 123.0 (15) | N2—C22—C7 | 114.51 (17) |
C10—C9—H9 | 118.8 (15) | N2—C22—C23 | 123.09 (19) |
C9—C10—H10 | 118.4 (17) | C23—C22—C7 | 122.37 (18) |
C11—C10—C9 | 120.5 (2) | C22—C23—H23 | 120.0 (16) |
C11—C10—H10 | 121.1 (17) | C24—C23—C22 | 118.4 (2) |
C10—C11—C12 | 120.95 (19) | C24—C23—H23 | 121.4 (16) |
C10—C11—H11 | 122.8 (16) | C23—C24—H24 | 120.2 (17) |
C12—C11—H11 | 116.2 (16) | C25—C24—C23 | 119.2 (2) |
C11—C12—H12 | 122.3 (16) | C25—C24—H24 | 120.7 (17) |
C13—C12—C11 | 118.25 (19) | C24—C25—H25 | 118.6 (17) |
C13—C12—H12 | 119.5 (16) | C26—C25—C24 | 118.5 (2) |
C8—C13—C14 | 106.09 (16) | C26—C25—H25 | 122.8 (17) |
C12—C13—C8 | 120.70 (19) | N2—C26—C25 | 123.7 (2) |
C12—C13—C14 | 132.98 (18) | N2—C26—H26 | 115.5 (16) |
O1—C14—O2 | 109.19 (15) | C25—C26—H26 | 120.8 (16) |
O1—C14—C13 | 103.65 (15) | ||
O1—C7—C8—C9 | 161.0 (2) | C8—C7—C22—N2 | −61.9 (2) |
O1—C7—C8—C13 | −24.38 (19) | C8—C7—C22—C23 | 116.4 (2) |
O1—C7—C22—N2 | −176.09 (17) | C8—C9—C10—C11 | −1.1 (3) |
O1—C7—C22—C23 | 2.2 (3) | C8—C13—C14—O1 | 24.79 (19) |
O1—C14—C15—N1 | 128.66 (18) | C8—C13—C14—O2 | −91.61 (18) |
O1—C14—C15—C16 | −52.5 (3) | C8—C13—C14—C15 | 147.19 (17) |
O2—C1—C2—C3 | 179.6 (2) | C9—C8—C13—C12 | 0.5 (3) |
O2—C1—C6—C5 | −179.70 (18) | C9—C8—C13—C14 | 175.61 (18) |
O2—C1—C6—C7 | −3.1 (3) | C9—C10—C11—C12 | 0.5 (3) |
O2—C14—C15—N1 | −113.89 (19) | C10—C11—C12—C13 | 0.6 (3) |
O2—C14—C15—C16 | 65.0 (2) | C11—C12—C13—C8 | −1.1 (3) |
O3—N1—C15—C14 | 178.80 (15) | C11—C12—C13—C14 | −174.7 (2) |
O3—N1—C15—C16 | −0.3 (2) | C12—C13—C14—O1 | −161.0 (2) |
N1—O3—C17—C16 | −1.0 (2) | C12—C13—C14—O2 | 82.6 (3) |
N1—O3—C17—C18 | 178.76 (19) | C12—C13—C14—C15 | −38.6 (3) |
N1—C15—C16—C17 | −0.3 (2) | C13—C8—C9—C10 | 0.6 (3) |
N1—C15—C16—C19 | −177.3 (2) | C13—C14—C15—N1 | 9.4 (3) |
N2—C22—C23—C24 | −0.7 (3) | C13—C14—C15—C16 | −171.76 (19) |
C1—O2—C14—O1 | −41.1 (2) | C14—O1—C7—C6 | −70.50 (17) |
C1—O2—C14—C13 | 71.8 (2) | C14—O1—C7—C8 | 40.23 (17) |
C1—O2—C14—C15 | −158.98 (16) | C14—O1—C7—C22 | 163.34 (15) |
C1—C2—C3—C4 | 0.3 (4) | C14—O2—C1—C2 | −174.96 (18) |
C1—C6—C7—O1 | 35.3 (2) | C14—O2—C1—C6 | 4.8 (3) |
C1—C6—C7—C8 | −72.2 (2) | C14—C15—C16—C17 | −179.22 (19) |
C1—C6—C7—C22 | 156.07 (18) | C14—C15—C16—C19 | 3.8 (4) |
C2—C1—C6—C5 | 0.0 (3) | C15—C16—C17—O3 | 0.8 (2) |
C2—C1—C6—C7 | 176.65 (19) | C15—C16—C17—C18 | −178.9 (3) |
C2—C3—C4—C5 | −0.3 (4) | C15—C16—C19—O4 | 171.3 (2) |
C3—C4—C5—C6 | 0.1 (3) | C15—C16—C19—O5 | −8.8 (3) |
C4—C5—C6—C1 | 0.0 (3) | C17—O3—N1—C15 | 0.8 (2) |
C4—C5—C6—C7 | −176.3 (2) | C17—C16—C19—O4 | −5.2 (3) |
C5—C6—C7—O1 | −148.31 (19) | C17—C16—C19—O5 | 174.7 (2) |
C5—C6—C7—C8 | 104.1 (2) | C19—O5—C20—C21 | −176.4 (2) |
C5—C6—C7—C22 | −27.6 (3) | C19—C16—C17—O3 | 178.15 (18) |
C6—C1—C2—C3 | −0.2 (3) | C19—C16—C17—C18 | −1.6 (4) |
C6—C7—C8—C9 | −89.3 (2) | C20—O5—C19—O4 | −8.2 (3) |
C6—C7—C8—C13 | 85.24 (18) | C20—O5—C19—C16 | 171.90 (18) |
C6—C7—C22—N2 | 65.2 (2) | C22—N2—C26—C25 | −0.3 (4) |
C6—C7—C22—C23 | −116.5 (2) | C22—C7—C8—C9 | 43.0 (3) |
C7—O1—C14—O2 | 76.13 (17) | C22—C7—C8—C13 | −142.41 (17) |
C7—O1—C14—C13 | −40.49 (17) | C22—C23—C24—C25 | −0.4 (4) |
C7—O1—C14—C15 | −168.89 (15) | C23—C24—C25—C26 | 1.1 (4) |
C7—C8—C9—C10 | 174.6 (2) | C24—C25—C26—N2 | −0.8 (4) |
C7—C8—C13—C12 | −174.74 (17) | C26—N2—C22—C7 | 179.4 (2) |
C7—C8—C13—C14 | 0.4 (2) | C26—N2—C22—C23 | 1.1 (3) |
C7—C22—C23—C24 | −178.9 (2) |
D—H···A | D—H | H···A | D···A | D—H···A |
C5—H5···N2 | 0.96 (2) | 2.42 (2) | 3.085 (3) | 125.8 (18) |
C23—H23···N1i | 1.00 (3) | 2.70 (3) | 3.669 (3) | 163 (2) |
C12—H12···O1ii | 0.94 (3) | 2.56 (3) | 3.469 (2) | 162 (2) |
C18—H18A···O4ii | 0.94 (4) | 2.71 (4) | 3.297 (3) | 121 (3) |
C18—H18B···O4 | 0.99 (4) | 2.38 (4) | 3.040 (3) | 123 (3) |
Symmetry codes: (i) x, −y+1/2, z−1/2; (ii) x, −y+1/2, z+1/2. |
Footnotes
‡Current address: Elite One Source, Nutritional Services, 1001 South 3rd West, Missoula, MT 59801 USA.
Acknowledgements
The authors thank the ALSAM Foundation for support of this work. The authors thank Dr Allen G. Oliver (University of Notre Dame) and Dr Jeanette A. Krause (University of Cincinnati) for the synchrotron data collected through the SCrALS (Service Crystallography at the Advanced Light Source) program at Beamline 12.2.1, Advanced Light Source (ALS), Lawrence Berkeley National Laboratory. The Advanced Light Source, is a DOE Office of Science User 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.
Funding information
Funding for this research was provided by: ALSAM Foundation Skaggs Scholar Grant (grant No. #1000233768 to Nicholas R. Natale); University of Montana (grant No. 325490 to Nicholas R. Natale).
References
Ando, Y., Hanaki, A., Sasaki, R., Ohmori, K. & Suzuki, K. (2017). Angew. Chem. Int. Ed. 56, 11460–11465. Web of Science CSD CrossRef CAS Google Scholar
Ando, Y., Tanaka, D., Sasaki, R., Ohmori, K. & Suzuki, K. (2019). Angew. Chem. Int. Ed. 58, 12507–12513. Web of Science CSD CrossRef CAS Google Scholar
Bruker (2016). SAINT and APEX3. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339–341. Web of Science CrossRef CAS IUCr Journals Google Scholar
Duncan, N. S., Beall, H. D., Kearns, A. K., Li, C. & Natale, N. R. (2014). Acta Cryst. E70, o315–o316. CSD CrossRef IUCr Journals Google Scholar
Filatov, M. A., Karuthedath, S., Polestshuk, P. M., Savoie, H., Flanagan, K. J., Sy, C., Sitte, E., Telitchko, M., Laquai, F., Boyle, R. W. & Senge, M. O. (2017). J. Am. Chem. Soc. 139, 6282–6285. Web of Science CSD CrossRef CAS PubMed Google Scholar
Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179. Web of Science CrossRef IUCr Journals Google Scholar
Han, X., Li, C., Mosher, M. D., Rider, K. C., Zhou, P., Crawford, R. L., Fusco, W., Paszczynski, A. & Natale, N. R. (2009). Bioorg. Med. Chem. 17, 1671–1680. Web of Science CrossRef PubMed CAS Google Scholar
Han, X., Li, C., Rider, K. C., Blumenfeld, A., Twamley, B. & Natale, N. R. (2002). Tetrahedron Lett. 43, 7673–7677. Web of Science CSD CrossRef CAS Google Scholar
Han, X., Twamley, B. & Natale, N. R. (2003). J. Heterocycl. Chem. 40, 539–545. Web of Science CSD CrossRef CAS Google Scholar
Klaper, M., Wessig, P. & Linker, T. (2016). Chem. Commun. 52, 1210–1213. Web of Science CrossRef CAS Google Scholar
Krause, L., Herbst-Irmer, R., Sheldrick, G. M. & Stalke, D. (2015). J. Appl. Cryst. 48, 3–10. Web of Science CSD CrossRef ICSD CAS IUCr Journals Google Scholar
Lauer, A., Dobryakov, A. L., Kovalenko, S. A., Fidder, H. & Heyne, K. (2011). Phys. Chem. Chem. Phys. 13, 8723–8732. Web of Science CrossRef CAS PubMed Google Scholar
Li, C., Campbell, M. J., Weaver, M. J., Duncan, N. S., Hunting, J. L. & Natale, N. R. (2013). Acta Cryst. E69, o1804–o1805. CSD CrossRef IUCr Journals Google Scholar
Li, C., Twamley, B. & Natale, N. R. (2006). Acta Cryst. E62, o854–o856. Web of Science CSD CrossRef CAS IUCr Journals Google Scholar
Li, C., Twamley, B. & Natale, N. R. (2008). J. Heterocycl. Chem. 45, 259–264. Web of Science CSD CrossRef CAS Google Scholar
McKinnon, J. J., Jayatilaka, D. & Spackman, M. A. (2007). Chem. Commun. pp. 3814–3816. Web of Science CrossRef Google Scholar
Mosher, M. D., Natale, N. R. & Vij, A. (1996). Acta Cryst. C52, 2513–2515. CSD CrossRef CAS Web of Science IUCr Journals Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Sheldrick, G. M. (2015). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Spackman, M. A. & Jayatilaka, D. (2009). CrystEngComm. 11, 19–32. Web of Science CrossRef CAS Google Scholar
Turner, M. J., McKinnon, J. J., Wolff, S. K., Grimwood, D. J., Spackman, P. R., Jayatilaka, D. & Spackman, M. A. (2017). CrystalExplorer17. University of Western Australia. https://hirshfeldsurface.net Google Scholar
Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. (2009). Science, 324, 1029–1033. Web of Science CrossRef PubMed CAS Google Scholar
Walker, M., Pohl, E., Herbst-Irmer, R., Gerlitz, M., Rohr, J. & Sheldrick, G. M. (1999). Acta Cryst. B55, 607–616. Web of Science CSD CrossRef CAS IUCr Journals Google Scholar
Weaver, M. J., Kearns, A. K., Stump, S., Li, C., Gajewski, M. P., Rider, K. C., Backos, D. S., Reigan, P. R., Beall, H. D. & Natale, N. R. (2015). Bioorg. Med. Chem. Lett. 25, 1765–1770. Web of Science CSD CrossRef CAS PubMed Google Scholar
Weaver, M. J., Stump, S., Campbell, M. J., Backos, D. S., Li, C., Reigan, P., Adams, E., Beall, H. D. & Natale, N. R. (2020). Bioorg. Med. Chem. 28, 115781. CrossRef PubMed Google Scholar
Westrip, S. P. (2010). J. Appl. Cryst. 43, 920–925. Web of Science CrossRef CAS IUCr Journals Google Scholar
This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.