(E)-13-(2-Bromo­phen­yl)micheliolide

Penthala, N.R.; Bommagani, S.; Janganati, V.; Parkin, S.; Crooks, P.A.

doi:10.1107/S1600536814002177

organic compounds

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 70| Part 3| March 2014| Pages o251-o252

doi:10.1107/S1600536814002177

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(E)-13-(2-Bromophenyl)micheliolide

Narsimha Reddy Penthala,^a Shobanbabu Bommagani,^a Venumadhav Janganati,^a Sean Parkin ^b and Peter A. Crooks ^a ^*

^aDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA, and ^bDepartment of Chemistry, University of Kentucky, Lexington, KY 40506, USA
^*Correspondence e-mail: pacrooks@uams.edu

(Received 20 November 2013; accepted 29 January 2014; online 5 February 2014)

The title compound, C₂₁H₂₃BrO₃ [systematic name: (3E,3aS,6Z,9R,9aS,9bS)-3-(2-bromobenzylidene)-9-hydroxy-6,9-dimethyl-3,3a,4,5,7,8,9,9a-octahydroazuleno[4,5-b]furan-2(9bH)-one] was prepared by the reaction of 1-bromo-2-iodobenzene with micheliolide [systematic name: (3aS,R,9aS,9bS,Z)-9-hydroxy-6,9-dimethyl-3-methylene-3,3a,4,5,7,8,9,9a-octahydroazuleno[4,5-b]furan-2(9bH)-one] under Heck reaction conditions. The title compound exhibits intramolecular O—H⋯O hydrogen bonding between the hydroxy group and the lactone ring O atom, forming a ring of graph-set motif S(6). The 2-bromophenyl group is trans to the lactone ring, indicating that this is the E isomer (geometry of the exocyclic C=C bond). The dihedral angle between the benzene ring of the 2-bromophenyl moiety and the mean plane of the lactone ring is 51.68 (7)°.

CCDC reference: 984233

Related literature

For the biological activity of micheliolide Michael addition compounds, see: Rodriguez et al. (1976 ); Sethi et al. (1984 ); Neelakantan et al. (2009 ); Zhang et al. (2012 ). For details of the Heck chemistry, see: Han et al. (2009 ). For the crystal structure of micheliolide, see: Acosta et al. (1991 ). For the crystal structure of a similar compound, see: Penthala et al. (2013 ).

Experimental

Crystal data

C₂₁H₂₃BrO₃
M_r = 403.30
Orthorhombic, P 2₁ 2₁ 2₁
a = 7.1617 (1) Å
b = 13.1615 (2) Å
c = 19.2306 (3) Å
V = 1812.65 (5) Å³
Z = 4
Mo Kα radiation
μ = 2.29 mm⁻¹
T = 90 K
0.20 × 0.20 × 0.15 mm

Data collection

Nonius KappaCCD diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 2008a ) T_min = 0.550, T_max = 0.714
48139 measured reflections
4148 independent reflections
3871 reflections with I > 2σ(I)
R_int = 0.047

Refinement

R[F² > 2σ(F²)] = 0.025
wR(F²) = 0.064
S = 1.04
4148 reflections
231 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.41 e Å⁻³
Δρ_min = −0.34 e Å⁻³
Absolute structure: Flack parameter determined using 1569 quotients [(I⁺)−(I⁻)]/[(I⁺)+(I⁻)] (Parsons et al., 2013 )
Absolute structure parameter: 0.032 (3)

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O3—H3⋯O2	0.77 (4)	2.26 (4)	2.883 (3)	139 (4)

Data collection: COLLECT (Nonius, 1998 ); cell refinement: SCALEPACK (Otwinowski & Minor, 2006 ); data reduction: DENZO-SMN (Otwinowski & Minor, 2006); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008b ); program(s) used to refine structure: SHELXL2013 (Sheldrick, 2008b); molecular graphics: XP in SHELXTL (Sheldrick, 2008b); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008b).

Supporting information

CCDC reference: 984233

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536814002177/sj5372sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536814002177/sj5372Isup2.hkl

Supporting information file. DOI: 10.1107/S1600536814002177/sj5372Isup3.cml

checkCIF report

Comment top

Micheliolide (MCL) belongs to the class of guaianolide sesquiterpene lactones, which are being developed for the treatment of cancer (Sethi et al., 1984 and Zhang et al., 2012). The exocyclic double bond in such sesquiterpenes is believed to be responsible for their biological properties because of its exceptional chemical reactivity with nucleophilic groups (Rodriguez et al., 1976). The MCL crystal structure was described by Acosta et al. (1991). Recently, micheliolide Michael addition analogs were reported as potent anti-leukemic agents (Zhang et al., 2012). In a recent communication we reported the crystal structure of (E)-13-(4-aminophenyl)parthenolide, a Heck reaction derivative of parthenolide (Penthala et al., 2013). Now, in continuation of our research on sesquiterpene lactones as anti-leukemic agents (Neelakantan et al., 2009), we are focusing on the synthesis of the title E-olefinic analogue of micheliolide, which was obtained from the reaction of micheliolide with 1-bromo-2-iodobenzene utilizing Heck chemistry (Han et al., 2009). In order to obtain detailed information on the structural conformation of the title compound and to establish the geometry of the exocyclic double bond, a single-crystal X-ray structure determination has been carried out.

Recrystallization of the title compound from hexanes gave colorless needles that were suitable for X-ray analysis. The title molecule, Fig. 1, contains a central seven-membered carbocyclic ring fused to a 5-membered carbocylic ring and a trans lactone ring. The two five-membered rings are in half-chair conformations, as reported in the literature for the parent compound, micheliolide (Acosta et al., 1991). The X-ray studies revealed that the title compound exhibits intramolecular O—H···O hydrogen bonding to form a ring of graph-set motif S(6). The 2-bromophenyl group is oriented trans to the lactone ring to form the E isomer (geometry of the exocyclic C═C bond). The H atom of the hydroxy group in the molecule forms an intramolecular hydrogen bond with the lactone ring oxygen atom. The dihedral angle between the benzene ring of the 2-bromophenyl group and the mean plane of the lactone ring is 51.68 (7)°.

Related literature top

For the biological activity of micheliolide Michael addition compounds, see: Rodriguez et al. (1976); Sethi et al. (1984); Neelakantan et al. (2009); Zhang et al. (2012). For details of the Heck chemistry, see: Han et al. (2009). For the crystal structure of micheliolide, see: Acosta et al. (1991). For the crystal structure of a similar compound, see: Penthala et al. (2013).

Experimental top

A mixture of micheliolide (prepared from parthenolide, Zhang et al., 2012) (50 mg, 0.20 mmol), triethylamine (60 mg, 0.61 mmol), and 1-bromo-2-iodobenzene (63 mg, 0.22 mmol) in dimethylformamide (1 ml) was treated with palladium(II) acetate (0.5 mg, 0.002 mmol) and then stirred at 353 K for 24 h. The reaction mixture was cooled to room temperature, water (8 ml) was added, and the mixture was extracted with ethyl acetate (10 ml x 3). The separated organics were dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified using silica flash chromatography (7:3, hexanes/EtOAc) to afford the title compound, which was recrystallized from hexanes as colorless needles suitable for X-ray analysis (65 mg, 80% yield; M·P: 421–423 K); ¹H NMR (400 MHz, CDCl₃): δ 7.70–7.70 (d, J=2.8 Hz, 1H), 7.62–7.64 (d, J=8.0 Hz, 1H), 7.22–7.35 (m, 3H, Ar—H and =CH), 3.89–3.94 (t, J=10 Hz, 20.4 Hz, 1H), 3.01–3.06 (t, J=8.8 Hz, 19.6 Hz, 1H), 2.73–2.76 (d, J=11.2 Hz, 1H), 2.71 (s, 1H), 2.35–2.41 (m, 1H), 2.01–2.21 (m, 1H), 1.76–1.89 (m, 3H), 1.61 (s, 3H), 1.32 (s, 3H), 1.00–1.04 (m, 1H) p.p.m.. ¹³C NMR (100 MHz, CDCl₃): δ 22.57, 23.69, 24.91, 29.86, 35.36, 38.23, 48.93, 58.99, 80.79, 124.14, 126.93, 129.86, 130.47, 130.55, 131.03, 131.50, 132.86, 134.54, 136.70, 170.68 p.p.m..

Computing details top

Data collection: COLLECT (Nonius, 1998); cell refinement: SCALEPACK (Otwinowski & Minor, 2006); data reduction: DENZO-SMN (Otwinowski & Minor, 2006); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008b); program(s) used to refine structure: SHELXL2013 (Sheldrick, 2008b); molecular graphics: XP in SHELXTL (Sheldrick, 2008b); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008b).

Figures top

Fig. 1. A view of the molecule with displacement ellipsoids drawn at the 50% probability level.

(3E,3aS,6Z,9R,9aS,9bS)-3-(2-Bromobenzylidene)-9-hydroxy-6,9-dimethyl-3,3a,4,5,7,8,9,9a-octahydroazuleno[4,5-b]furan-2(9bH)-one top

Crystal data top

C₂₁H₂₃BrO₃	D_x = 1.478 Mg m⁻³
M_r = 403.30	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P2₁2₁2₁	Cell parameters from 127083 reflections
a = 7.1617 (1) Å	θ = 1.0–27.5°
b = 13.1615 (2) Å	µ = 2.29 mm⁻¹
c = 19.2306 (3) Å	T = 90 K
V = 1812.65 (5) Å³	Block, cut from needle, colourless
Z = 4	0.20 × 0.20 × 0.15 mm
F(000) = 832

Data collection top

Nonius KappaCCD diffractometer	4148 independent reflections
Radiation source: fine-focus sealed-tube	3871 reflections with I > 2σ(I)
Detector resolution: 9.1 pixels mm^-1	R_int = 0.047
φ and ω scans at fixed χ = 55°	θ_max = 27.5°, θ_min = 1.9°
Absorption correction: multi-scan (SADABS; Sheldrick, 2008a)	h = −9→9
T_min = 0.550, T_max = 0.714	k = −17→17
48139 measured reflections	l = −24→24

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.025	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.064	w = 1/[σ²(F_o²) + (0.0352P)² + 0.4253P] where P = (F_o² + 2F_c²)/3
S = 1.04	(Δ/σ)_max = 0.001
4148 reflections	Δρ_max = 0.41 e Å⁻³
231 parameters	Δρ_min = −0.34 e Å⁻³
0 restraints	Absolute structure: Flack parameter determined using 1569 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.032 (3)

Crystal data top

C₂₁H₂₃BrO₃	V = 1812.65 (5) Å³
M_r = 403.30	Z = 4
Orthorhombic, P2₁2₁2₁	Mo Kα radiation
a = 7.1617 (1) Å	µ = 2.29 mm⁻¹
b = 13.1615 (2) Å	T = 90 K
c = 19.2306 (3) Å	0.20 × 0.20 × 0.15 mm

Data collection top

Nonius KappaCCD diffractometer	4148 independent reflections
Absorption correction: multi-scan (SADABS; Sheldrick, 2008a)	3871 reflections with I > 2σ(I)
T_min = 0.550, T_max = 0.714	R_int = 0.047
48139 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.025	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.064	Δρ_max = 0.41 e Å⁻³
S = 1.04	Δρ_min = −0.34 e Å⁻³
4148 reflections	Absolute structure: Flack parameter determined using 1569 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
231 parameters	Absolute structure parameter: 0.032 (3)
0 restraints

Special details top

Experimental. The crystal was mounted with polyisobutene oil on the tip of a fine glass fibre, fastened in a copper mounting pin with electrical solder. It was placed directly into the cold stream of a liquid nitrogen based cryostat.

Diffraction data were collected with the crystal at 90 K, which is standard practice in this laboratory for the majority of flash-cooled crystals.

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
Br1	0.79983 (4)	−0.11654 (2)	0.35920 (2)	0.03215 (9)
O1	0.7715 (3)	0.26157 (14)	0.45446 (10)	0.0248 (4)
O2	0.5251 (3)	0.34175 (14)	0.40803 (9)	0.0215 (4)
O3	0.3499 (3)	0.53339 (15)	0.43985 (11)	0.0285 (5)
H3	0.434 (6)	0.498 (3)	0.444 (2)	0.043*
C1	0.0338 (3)	0.3743 (2)	0.33548 (13)	0.0202 (5)
C2	−0.0575 (4)	0.4794 (2)	0.33076 (16)	0.0252 (6)
H2A	−0.0553	0.5046	0.2823	0.030*
H2B	−0.1887	0.4765	0.3468	0.030*
C3	0.0577 (4)	0.5486 (2)	0.37792 (14)	0.0243 (6)
H3A	0.0633	0.6184	0.3589	0.029*
H3B	0.0037	0.5512	0.4253	0.029*
C4	0.2513 (4)	0.50008 (19)	0.37900 (13)	0.0208 (5)
C5	0.2022 (3)	0.38520 (18)	0.38337 (12)	0.0185 (4)
H5	0.1602	0.3704	0.4319	0.022*
C6	0.3602 (3)	0.31433 (18)	0.36651 (14)	0.0192 (5)
H6	0.3917	0.3211	0.3161	0.023*
C7	0.3212 (4)	0.20208 (18)	0.38266 (13)	0.0198 (5)
H7	0.2314	0.1984	0.4224	0.024*
C8	0.2325 (4)	0.1511 (2)	0.31966 (14)	0.0237 (6)
H8A	0.2408	0.0764	0.3251	0.028*
H8B	0.3031	0.1702	0.2774	0.028*
C9	0.0275 (4)	0.1814 (2)	0.31045 (16)	0.0259 (6)
H9A	−0.0413	0.1538	0.3509	0.031*
H9B	−0.0193	0.1449	0.2690	0.031*
C10	−0.0321 (4)	0.2927 (2)	0.30252 (14)	0.0212 (5)
C11	0.5102 (4)	0.1654 (2)	0.40740 (13)	0.0201 (5)
C12	0.6223 (4)	0.2566 (2)	0.42595 (13)	0.0204 (5)
C13	0.5791 (4)	0.07309 (19)	0.42009 (13)	0.0210 (5)
H13	0.7092	0.0697	0.4295	0.025*
C14	−0.2025 (4)	0.3016 (2)	0.25629 (14)	0.0257 (5)
H14A	−0.2471	0.3720	0.2565	0.039*
H14B	−0.3011	0.2567	0.2738	0.039*
H14C	−0.1695	0.2817	0.2087	0.039*
C15	0.3630 (4)	0.5270 (2)	0.31404 (15)	0.0255 (6)
H15A	0.3776	0.6010	0.3111	0.038*
H15B	0.2969	0.5024	0.2727	0.038*
H15C	0.4864	0.4951	0.3165	0.038*
C16	0.4774 (4)	−0.0247 (2)	0.42131 (13)	0.0204 (5)
C17	0.5616 (4)	−0.1163 (2)	0.40254 (13)	0.0220 (5)
C18	0.4756 (4)	−0.2095 (2)	0.41364 (14)	0.0252 (6)
H18	0.5356	−0.2707	0.3999	0.030*
C19	0.3015 (5)	−0.21243 (19)	0.44500 (14)	0.0261 (6)
H19	0.2434	−0.2759	0.4542	0.031*
C20	0.2116 (4)	−0.1224 (2)	0.46308 (13)	0.0251 (5)
H20	0.0909	−0.1244	0.4835	0.030*
C21	0.2988 (4)	−0.02945 (19)	0.45117 (13)	0.0228 (5)
H21	0.2364	0.0317	0.4634	0.027*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Br1	0.03169 (14)	0.02821 (14)	0.03656 (15)	0.00934 (12)	0.00802 (12)	0.00322 (13)
O1	0.0264 (10)	0.0225 (9)	0.0254 (9)	−0.0003 (8)	−0.0026 (8)	0.0020 (8)
O2	0.0249 (9)	0.0140 (8)	0.0256 (9)	−0.0014 (7)	−0.0045 (7)	0.0001 (7)
O3	0.0383 (12)	0.0152 (9)	0.0319 (11)	0.0016 (8)	−0.0109 (9)	−0.0040 (8)
C1	0.0231 (11)	0.0163 (12)	0.0212 (11)	−0.0009 (10)	0.0027 (9)	0.0025 (10)
C2	0.0257 (13)	0.0145 (12)	0.0355 (15)	0.0004 (10)	−0.0034 (11)	0.0028 (11)
C3	0.0301 (13)	0.0148 (12)	0.0281 (14)	0.0020 (10)	0.0017 (11)	0.0004 (10)
C4	0.0289 (12)	0.0112 (11)	0.0224 (13)	−0.0009 (9)	−0.0046 (10)	−0.0001 (9)
C5	0.0231 (11)	0.0120 (10)	0.0204 (10)	−0.0016 (12)	0.0008 (9)	0.0005 (9)
C6	0.0242 (11)	0.0148 (11)	0.0185 (12)	−0.0012 (9)	−0.0028 (10)	−0.0006 (10)
C7	0.0258 (12)	0.0119 (11)	0.0218 (12)	−0.0010 (10)	0.0007 (10)	−0.0009 (9)
C8	0.0304 (14)	0.0162 (12)	0.0246 (13)	0.0016 (10)	−0.0023 (11)	−0.0038 (10)
C9	0.0290 (13)	0.0172 (13)	0.0316 (14)	0.0001 (11)	−0.0044 (11)	−0.0055 (11)
C10	0.0229 (12)	0.0187 (13)	0.0221 (13)	0.0003 (10)	0.0010 (10)	0.0000 (10)
C11	0.0261 (13)	0.0175 (13)	0.0168 (12)	0.0002 (10)	0.0008 (10)	0.0004 (10)
C12	0.0254 (13)	0.0176 (12)	0.0182 (12)	−0.0011 (10)	0.0006 (10)	0.0013 (10)
C13	0.0255 (13)	0.0184 (12)	0.0191 (12)	−0.0010 (10)	0.0022 (10)	0.0006 (10)
C14	0.0236 (12)	0.0222 (13)	0.0312 (14)	−0.0014 (12)	−0.0005 (12)	−0.0016 (11)
C15	0.0262 (13)	0.0179 (13)	0.0323 (15)	−0.0013 (10)	−0.0030 (11)	0.0043 (11)
C16	0.0277 (13)	0.0157 (12)	0.0179 (12)	0.0002 (10)	−0.0028 (11)	0.0009 (10)
C17	0.0243 (12)	0.0205 (12)	0.0211 (12)	0.0033 (12)	−0.0017 (9)	0.0009 (11)
C18	0.0360 (15)	0.0148 (13)	0.0247 (14)	0.0045 (11)	−0.0032 (12)	−0.0021 (11)
C19	0.0361 (14)	0.0163 (12)	0.0259 (13)	−0.0040 (13)	−0.0051 (14)	0.0014 (10)
C20	0.0275 (12)	0.0214 (12)	0.0264 (12)	−0.0042 (13)	−0.0001 (11)	0.0025 (11)
C21	0.0279 (12)	0.0155 (12)	0.0251 (12)	0.0024 (12)	−0.0004 (13)	0.0019 (10)

Geometric parameters (Å, º) top

Br1—C17	1.899 (3)	C8—H8B	0.9900
O1—C12	1.203 (3)	C9—C10	1.533 (4)
O2—C12	1.364 (3)	C9—H9A	0.9900
O2—C6	1.470 (3)	C9—H9B	0.9900
O3—C4	1.435 (3)	C10—C14	1.514 (4)
O3—H3	0.77 (4)	C11—C13	1.335 (4)
C1—C10	1.333 (4)	C11—C12	1.487 (4)
C1—C5	1.525 (3)	C13—C16	1.479 (4)
C1—C2	1.532 (4)	C13—H13	0.9500
C2—C3	1.527 (4)	C14—H14A	0.9800
C2—H2A	0.9900	C14—H14B	0.9800
C2—H2B	0.9900	C14—H14C	0.9800
C3—C4	1.527 (4)	C15—H15A	0.9800
C3—H3A	0.9900	C15—H15B	0.9800
C3—H3B	0.9900	C15—H15C	0.9800
C4—C15	1.525 (4)	C16—C17	1.396 (4)
C4—C5	1.555 (3)	C16—C21	1.403 (4)
C5—C6	1.502 (3)	C17—C18	1.389 (4)
C5—H5	1.0000	C18—C19	1.386 (4)
C6—C7	1.535 (3)	C18—H18	0.9500
C6—H6	1.0000	C19—C20	1.393 (4)
C7—C11	1.514 (4)	C19—H19	0.9500
C7—C8	1.524 (4)	C20—C21	1.392 (4)
C7—H7	1.0000	C20—H20	0.9500
C8—C9	1.532 (4)	C21—H21	0.9500
C8—H8A	0.9900

C12—O2—C6	110.22 (19)	C8—C9—H9A	106.9
C4—O3—H3	106 (3)	C10—C9—H9A	106.9
C10—C1—C5	130.0 (2)	C8—C9—H9B	106.9
C10—C1—C2	123.2 (2)	C10—C9—H9B	106.9
C5—C1—C2	106.8 (2)	H9A—C9—H9B	106.7
C3—C2—C1	105.8 (2)	C1—C10—C14	120.2 (2)
C3—C2—H2A	110.6	C1—C10—C9	128.6 (2)
C1—C2—H2A	110.6	C14—C10—C9	110.8 (2)
C3—C2—H2B	110.6	C13—C11—C12	119.4 (2)
C1—C2—H2B	110.6	C13—C11—C7	132.7 (2)
H2A—C2—H2B	108.7	C12—C11—C7	107.5 (2)
C4—C3—C2	104.4 (2)	O1—C12—O2	121.6 (2)
C4—C3—H3A	110.9	O1—C12—C11	129.3 (2)
C2—C3—H3A	110.9	O2—C12—C11	109.1 (2)
C4—C3—H3B	110.9	C11—C13—C16	127.8 (2)
C2—C3—H3B	110.9	C11—C13—H13	116.1
H3A—C3—H3B	108.9	C16—C13—H13	116.1
O3—C4—C15	109.8 (2)	C10—C14—H14A	109.5
O3—C4—C3	109.3 (2)	C10—C14—H14B	109.5
C15—C4—C3	111.6 (2)	H14A—C14—H14B	109.5
O3—C4—C5	111.4 (2)	C10—C14—H14C	109.5
C15—C4—C5	112.9 (2)	H14A—C14—H14C	109.5
C3—C4—C5	101.7 (2)	H14B—C14—H14C	109.5
C6—C5—C1	114.0 (2)	C4—C15—H15A	109.5
C6—C5—C4	115.0 (2)	C4—C15—H15B	109.5
C1—C5—C4	103.7 (2)	H15A—C15—H15B	109.5
C6—C5—H5	107.9	C4—C15—H15C	109.5
C1—C5—H5	107.9	H15A—C15—H15C	109.5
C4—C5—H5	107.9	H15B—C15—H15C	109.5
O2—C6—C5	109.59 (19)	C17—C16—C21	117.4 (2)
O2—C6—C7	105.82 (19)	C17—C16—C13	122.3 (2)
C5—C6—C7	114.6 (2)	C21—C16—C13	119.7 (2)
O2—C6—H6	108.9	C18—C17—C16	122.1 (2)
C5—C6—H6	108.9	C18—C17—Br1	117.7 (2)
C7—C6—H6	108.9	C16—C17—Br1	120.2 (2)
C11—C7—C8	118.8 (2)	C19—C18—C17	119.3 (3)
C11—C7—C6	102.0 (2)	C19—C18—H18	120.3
C8—C7—C6	109.8 (2)	C17—C18—H18	120.3
C11—C7—H7	108.6	C18—C19—C20	120.1 (2)
C8—C7—H7	108.6	C18—C19—H19	120.0
C6—C7—H7	108.6	C20—C19—H19	120.0
C7—C8—C9	112.1 (2)	C21—C20—C19	119.9 (2)
C7—C8—H8A	109.2	C21—C20—H20	120.0
C9—C8—H8A	109.2	C19—C20—H20	120.0
C7—C8—H8B	109.2	C20—C21—C16	121.0 (3)
C9—C8—H8B	109.2	C20—C21—H21	119.5
H8A—C8—H8B	107.9	C16—C21—H21	119.5
C8—C9—C10	121.8 (2)

C10—C1—C2—C3	178.0 (2)	C2—C1—C10—C14	1.5 (4)
C5—C1—C2—C3	−1.5 (3)	C5—C1—C10—C9	8.9 (5)
C1—C2—C3—C4	26.5 (3)	C2—C1—C10—C9	−170.6 (3)
C2—C3—C4—O3	−158.4 (2)	C8—C9—C10—C1	−39.4 (4)
C2—C3—C4—C15	80.0 (3)	C8—C9—C10—C14	147.9 (3)
C2—C3—C4—C5	−40.6 (3)	C8—C7—C11—C13	−48.2 (4)
C10—C1—C5—C6	31.2 (4)	C6—C7—C11—C13	−169.0 (3)
C2—C1—C5—C6	−149.3 (2)	C8—C7—C11—C12	138.5 (2)
C10—C1—C5—C4	157.0 (3)	C6—C7—C11—C12	17.7 (3)
C2—C1—C5—C4	−23.5 (3)	C6—O2—C12—O1	173.0 (2)
O3—C4—C5—C6	−79.2 (3)	C6—O2—C12—C11	−9.5 (3)
C15—C4—C5—C6	44.9 (3)	C13—C11—C12—O1	−3.0 (4)
C3—C4—C5—C6	164.5 (2)	C7—C11—C12—O1	171.3 (3)
O3—C4—C5—C1	155.6 (2)	C13—C11—C12—O2	179.7 (2)
C15—C4—C5—C1	−80.3 (2)	C7—C11—C12—O2	−6.0 (3)
C3—C4—C5—C1	39.3 (2)	C12—C11—C13—C16	164.5 (2)
C12—O2—C6—C5	145.0 (2)	C7—C11—C13—C16	−8.2 (5)
C12—O2—C6—C7	21.0 (3)	C11—C13—C16—C17	148.9 (3)
C1—C5—C6—O2	171.08 (19)	C11—C13—C16—C21	−40.2 (4)
C4—C5—C6—O2	51.4 (3)	C21—C16—C17—C18	−1.1 (4)
C1—C5—C6—C7	−70.1 (3)	C13—C16—C17—C18	170.0 (3)
C4—C5—C6—C7	170.2 (2)	C21—C16—C17—Br1	178.06 (18)
O2—C6—C7—C11	−22.9 (2)	C13—C16—C17—Br1	−10.8 (3)
C5—C6—C7—C11	−143.8 (2)	C16—C17—C18—C19	−0.7 (4)
O2—C6—C7—C8	−149.8 (2)	Br1—C17—C18—C19	−179.9 (2)
C5—C6—C7—C8	89.3 (3)	C17—C18—C19—C20	2.0 (4)
C11—C7—C8—C9	168.4 (2)	C18—C19—C20—C21	−1.6 (4)
C6—C7—C8—C9	−74.9 (3)	C19—C20—C21—C16	−0.3 (4)
C7—C8—C9—C10	57.4 (4)	C17—C16—C21—C20	1.6 (4)
C5—C1—C10—C14	−179.1 (2)	C13—C16—C21—C20	−169.8 (2)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O2	0.77 (4)	2.26 (4)	2.883 (3)	139 (4)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O2	0.77 (4)	2.26 (4)	2.883 (3)	139 (4)

Acknowledgements

This work was supported by the NIH/NCI [grant No. CA158275].

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