(2RS,5SR,6SR)-Methyl 4-{cis-2-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy­methyl]-6-hydroxy-3-phenylmorpholino}­benzene­sulfinate

The title compound, C₃₀H₃₄FNO₇S, is a key inter­mediate in the design of dual 5-LOX (5-lipoxygenase)/COX-2 (cyclo­oxygenase-2) inhibitors. The compound crystallizes as a racemate. Linear hydrogen-bonded chains are aligned along the [201] direction, and stacked [pi]-[pi] inter­actions and C-H...O contacts stabilize the crystal structure.

S1. Comment

A promising new strategy in cancer chemoprevention is being developed based on the design of inhibitors of the two major arachidonic acid metabolizing enzymes, namely type-2 cyclooxygenase (COX-2) and 5-lipoxygenase (5-LOX). These enzymes are indeed up-regulated in many tumours and some of their inhibitors exhibit marked proapoptotic and/or anti-angiogenic activities (Zha et al., 2004; Hoque et al., 2005). For the development of new therapeutic treatments, therefore, it is of interest to design dual COX-2/5-LOX inhibitors (Charlier et al., 2003; Romano et al., 2003; Ye et al., 2005; Li et al., 2005). Taking into account the key pharmacophoric elements of Celecoxib, a COX-2 selective inhibitor known for its highly potent antitumour activity (Kismet et al., 2004), and those of ZD-2138, a referenced competitive 5-LOX inhibitor (Crawley et al., 1992), a series of novel compounds has been explored (Barbey et al., 2002; Pommery et al., 2004; Charlier et al., 2004). As part of this continuing project, the importance of the central pyrazole ring of Celecoxib on antiproliferative activity has been investigated by replacement with diverse saturated rings. The present paper reports the structure of the title compound, (I), a key intermediate hydroxymorpholine.

Briefly, compound (I) was synthesized by reduction of the corresponding morpholinedione using borane–dimethylsulfide complex in tetrahydrofuran. The morpholinedione itself resulted from the cyclization of the aminoalcohol with oxalyl chloride. The NMR spectrum of compound (I) does not allow us to determine the position of the hydroxyl group on the morpholine. However, in order to delineate relevant structure–activity relationships, it is essential to determine the position of this hydrophilic moiety. It might very likely influence the binding of the compound to COX-2 as well as 5-LOX, through the formation of hydrogen bonds within the active sites. Thus, in order to elucidate the structure of (I), we realised the present X-ray crystal structure analysis.

Compound (I) crystallizes in the monoclinic space group P2₁/c with one molecule in the asymmetric unit. Its molecular structure and conformation are shown in Fig. 1. The substituents of the morpholine ring are in an all-cis orientation. The morpholine and tetrahydropyran rings both adopt chair conformations. The 5-LOX fragment and the hydroxyl group are positioned equatorially, whereas the unsubstituted phenyl ring (ring B) lies in an axial position. Compound (I) crystallizes as a racemate: both enantiomers (2R,5S,6S) and (2S,5R,6R) are present in the unit cell.

In the crystal packing of (I), hydrogen bonds (weak and strong) and π–π interactions exist between symmetry-related molecules. In particular, a strong hydrogen bond occurs between the hydroxyl atom H7 and the sulfonyl atom O15, forming infinite chains running along the [201] direction (Fig. 2, Table 1). Stacked π–π interactions between phenyl rings A and C reinforce the cohesion between the chains (Fig. 2). The stacking geometry is such that rings A and C of one molecule are superimposed on rings C and A of two symmetry-related molecules, at (x, 1/2 − y, −1/2 + z) and (x, 1/2 − y, 1/2 + z), respectively. The distance between the centroids of rings A and C is 3.834 (2) Å and the dihedral angle between the planes is 18.9°. Several weak C—H···O and C—H···F contacts (Desiraju et al., 1999) further stabilize the packing of (I) (Table 1), yielding a three-dimensional assembly. A weak intramolecular hydrogen bond, involving the phenyl atom H12 and the sulfonyl atom O16, influences the conformation of the sulfonyl moiety with respect to the phenyl ring (Table 1).

In order to assess the influence of stereochemistry on COX-2 binding, a preliminary docking study was performed. Both enantiomers were manually docked inside the COX-2 active site and compared with the conformation of SC-558, a tricyclic sulfonamide parent to Celecoxib, co-crystallized with murine COX-2 (PDB code 6COX; Kurumbail et al., 1996). The two vicinal phenyl rings (rings A and B) and the morpholine N atom were correctly aligned with their counterparts in SC-558. A s illustrated in Fig. 3, the COX-2 pharmacophore in both enantiomers is able to bind the COX-2 active site in a manner similar to that of SC-558. This suggests that phenyl ring B could occupy the upper part of the channel, while the sulfonylphenyl ring A could accommodate the hydrophilic side pocket in the COX-2 active site and thus form π–π interactions with Tyr355 and hydrogen bonds with polar residues such as Arg513 and His90. In both enantiomers, the 5-LOX pharmacophoric group could be oriented to point towards the upper part of the channel and could fit a small lipophilic cavity present in the N/E region of the active site and bordered by, among other residues, Phe209, Val228 and Leu534. In the (2R,5S,6S) enantiomer, the hydroxyl moiety on the morpholine ring points in the direction of hydrophobic residues at the bottom of the cavity, such as Val349 and Leu359. In contrast, in the (2S,5R,6R) enantiomer, the hydroxyl moiety is oriented towards Arg120 and could realise a strong hydrogen bond with this residue, stabilizing the complex.

This preliminary study suggests an influence of the stereochemistry on COX-2 affinity. The crystal structure reported here will be the starting point for further binding-mode studies into the COX-2 active site by means of automated docking algorithms.

S2. Experimental

Crystals of compound (I) suitable for X-ray diffraction analysis were obtained by slow evaporation of a solution in a mixture of diethyl ether and methanol (1:1).

S3. Refinement

All H atoms were placed in geometrically idealized positions and allowed to ride on their parent atoms. For the methyl and hydroxyl groups, the C—H and O—H distances were fixed at 0.96 and 0.82 Å, respectively, with U_iso(H) = 1.5U_eq(C). Aromatic and aliphatic C—H distances were fixed at 0.93 Å, with U_iso(H) = 1.2U_eq(C). It should be noted that the hydroxyl atom H7 was initially located in a difference Fourier map and then treated as a riding atom.

Computing details

Data collection: CAD-4 MACH3 (Nonius, 2000); cell refinement: CAD-4 MACH3; data reduction: HELENA (Spek, 1997); program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek, 2003); software used to prepare material for publication: enCIFer (Allen et al., 2004).

Figures

	Fig. 1. A view of compound (I) [(2R,5S,6S) enantiomer], showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level and H atoms have been omitted for clarity.
	Fig. 2. A packing diagram for (I), illustrating the π–π interactions between rings A and C and the strong hydrogen-bonding network (dashed grey lines), forming infinite chains along the [201] direction. [Symmetry codes: (i) x + 1, 1/2 − y, 1/2 + z; (ii) x − 1, 1/2 − y, z − 1/2; (iii) x, 1/2 − y, z − 1/2; (vi) x, 1/2 − y, z + 1/2.]
	Fig. 3. A superimposition of compound (I) [(2R,5S,6S) enantiomer drawn as sticks and (2S,5R,6R) enantiomer in balls and sticks] onto the co-crystallized conformation of SC-558 (in sticks). H atoms have been omitted for clarity and the O atom of the hydroxyl moiety of both enantiomers has been circled.

Methyl 4-{cis-2-[3-fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran- 4-yl)phenoxymethyl]-6-hydroxy-3-phenylmorpholino}benzenesulfinate

Crystal data

C30H34FNO7S	F(000) = 1208
Mr = 571.64	Dx = 1.362 Mg m^−3
Monoclinic, P21/c	Cu Kα radiation, λ = 1.54178 Å
Hall symbol: -P 2ybc	Cell parameters from 21 reflections
a = 7.151 (3) Å	θ = 20.0–29.9°
b = 21.430 (4) Å	µ = 1.51 mm^−1
c = 18.274 (3) Å	T = 293 K
β = 95.479 (10)°	Needle, colourless
V = 2787.6 (14) Å^3	0.40 × 0.08 × 0.06 mm
Z = 4

Data collection

Enraf–Nonius CAD-4 diffractometer	4215 reflections with I > 2σ(I)
Radiation source: long fine-focus sealed tube	Rint = 0.037
Graphite monochromator	θmax = 75.2°, θmin = 3.2°
θ/2θ scans	h = −8→0
Absorption correction: analytical (de Meulenaer & Tompa, 1965)	k = −26→0
Tmin = 0.584, Tmax = 0.915	l = −22→22
6196 measured reflections	3 standard reflections every 200 reflections
5730 independent reflections	intensity decay: 4%

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)] = 0.061	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.176	H-atom parameters constrained
S = 1.04	w = 1/[σ^2(Fo^2) + (0.0848P)^2 + 2.272P] where P = (Fo^2 + 2Fc^2)/3
5730 reflections	(Δ/σ)max < 0.001
351 parameters	Δρmax = 1.00 e Å^−3
57 restraints	Δρmin = −0.45 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
N4	0.9139 (3)	0.20280 (11)	0.34146 (11)	0.0353 (5)
C5	0.8395 (4)	0.17922 (14)	0.40955 (13)	0.0369 (5)
H5	0.7112	0.1954	0.4094	0.044*
C6	0.9542 (4)	0.20831 (13)	0.47663 (13)	0.0345 (5)
H6	0.9257	0.2530	0.4781	0.041*
O1	1.1499 (3)	0.20078 (9)	0.47283 (9)	0.0378 (4)
C3	1.1176 (4)	0.20880 (15)	0.34106 (14)	0.0422 (7)
H3A	1.1452	0.2356	0.3007	0.051*
H3B	1.1714	0.1681	0.3332	0.051*
C2	1.2069 (4)	0.23569 (15)	0.41243 (14)	0.0408 (6)
H2	1.1707	0.2796	0.4168	0.049*
O7	1.3970 (3)	0.23082 (12)	0.41284 (12)	0.0593 (6)
H7	1.4479	0.2510	0.4473	0.077*
C8	0.8095 (4)	0.18955 (12)	0.27494 (13)	0.0340 (5)
C9	0.8938 (4)	0.18135 (15)	0.20944 (15)	0.0434 (6)
H9	1.0236	0.1847	0.2101	0.052*
C10	0.7881 (4)	0.16836 (14)	0.14399 (15)	0.0432 (6)
H10	0.8467	0.1627	0.1012	0.052*
C11	0.5950 (4)	0.16371 (12)	0.14217 (13)	0.0359 (5)
C12	0.5083 (4)	0.17306 (14)	0.20582 (15)	0.0398 (6)
H12	0.3782	0.1707	0.2044	0.048*
C13	0.6132 (4)	0.18585 (14)	0.27128 (14)	0.0392 (6)
H13	0.5529	0.1921	0.3136	0.047*
S14	0.45661 (11)	0.14759 (3)	0.06007 (4)	0.0414 (2)
O15	0.5469 (3)	0.17464 (11)	0.00039 (11)	0.0553 (6)
O16	0.2660 (3)	0.16510 (12)	0.06801 (13)	0.0622 (7)
C17	0.4646 (5)	0.06656 (15)	0.04832 (18)	0.0573 (9)
H17A	0.4076	0.0464	0.0875	0.086*
H17B	0.5930	0.0533	0.0489	0.086*
H17C	0.3975	0.0555	0.0021	0.086*
C18	0.8252 (5)	0.10845 (15)	0.41168 (14)	0.0465 (5)
C19	0.9788 (5)	0.06965 (16)	0.40681 (19)	0.0564 (5)
H19	1.0963	0.0870	0.4022	0.068*
C20	0.9594 (7)	0.00528 (19)	0.4087 (2)	0.0747 (7)
H20	1.0638	−0.0203	0.4063	0.090*
C21	0.7871 (7)	−0.02040 (17)	0.4140 (2)	0.0736 (9)
H21	0.7739	−0.0636	0.4136	0.088*
C22	0.6343 (7)	0.01619 (18)	0.4197 (2)	0.0747 (7)
H22	0.5178	−0.0021	0.4238	0.090*
C23	0.6513 (5)	0.08162 (16)	0.41960 (19)	0.0564 (5)
H23	0.5472	0.1067	0.4248	0.068*
C24	0.9162 (4)	0.17935 (14)	0.54926 (14)	0.0376 (6)
H24A	0.9484	0.1354	0.5497	0.045*
H24B	0.9916	0.1997	0.5893	0.045*
O25	0.7225 (3)	0.18689 (10)	0.55789 (10)	0.0419 (5)
C26	0.6599 (4)	0.16662 (12)	0.62224 (14)	0.0353 (5)
C27	0.4738 (4)	0.18140 (13)	0.63001 (15)	0.0395 (5)
H27	0.3987	0.2021	0.5933	0.047*
C28	0.4063 (4)	0.16374 (15)	0.69526 (17)	0.0448 (6)
C29	0.5088 (4)	0.13206 (15)	0.75031 (17)	0.0462 (6)
H29	0.4562	0.1216	0.7933	0.055*
C30	0.6934 (4)	0.11575 (13)	0.74076 (14)	0.0377 (5)
C31	0.7696 (4)	0.13417 (13)	0.67672 (14)	0.0364 (5)
H31	0.8940	0.1248	0.6704	0.044*
F32	0.2256 (3)	0.18026 (11)	0.70522 (11)	0.0676 (6)
C33	0.8038 (4)	0.07769 (14)	0.80086 (15)	0.0418 (5)
C34	0.9975 (5)	0.05715 (19)	0.78224 (18)	0.0594 (8)
H34A	1.0689	0.0934	0.7695	0.071*
H34B	0.9844	0.0295	0.7400	0.071*
C35	1.1031 (7)	0.0234 (2)	0.8473 (2)	0.0837 (14)
H35A	1.0345	−0.0139	0.8584	0.100*
H35B	1.2257	0.0107	0.8341	0.100*
O36	1.1256 (4)	0.06187 (17)	0.91054 (15)	0.0864 (10)
C37	0.9473 (6)	0.0792 (2)	0.93276 (19)	0.0712 (11)
H37A	0.9658	0.1055	0.9761	0.085*
H37B	0.8810	0.0420	0.9459	0.085*
C38	0.8287 (5)	0.11381 (17)	0.87316 (16)	0.0555 (8)
H38A	0.8870	0.1537	0.8648	0.067*
H38B	0.7061	0.1220	0.8897	0.067*
O39	0.6920 (4)	0.02433 (11)	0.81732 (12)	0.0593 (6)
C40	0.6489 (9)	−0.0176 (2)	0.7584 (3)	0.1030 (19)
H40A	0.6201	0.0055	0.7138	0.154*
H40B	0.5423	−0.0425	0.7681	0.154*
H40C	0.7548	−0.0443	0.7535	0.154*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
N4	0.0298 (12)	0.0513 (13)	0.0244 (10)	−0.0024 (10)	−0.0002 (8)	0.0014 (9)
C5	0.0293 (13)	0.0567 (10)	0.0241 (9)	−0.0005 (8)	0.0000 (9)	0.0036 (10)
C6	0.0328 (14)	0.0438 (13)	0.0264 (10)	0.0054 (10)	−0.0005 (9)	0.0016 (9)
O1	0.0331 (10)	0.0498 (11)	0.0294 (9)	0.0033 (8)	−0.0025 (7)	−0.0008 (8)
C3	0.0384 (16)	0.0581 (18)	0.0299 (12)	−0.0088 (13)	0.0017 (11)	0.0002 (11)
C2	0.0355 (11)	0.0517 (16)	0.0340 (12)	−0.0041 (12)	−0.0019 (11)	−0.0019 (11)
O7	0.0386 (10)	0.0884 (18)	0.0504 (12)	−0.0031 (11)	0.0021 (10)	−0.0225 (12)
C8	0.0363 (10)	0.0376 (13)	0.0271 (9)	−0.0009 (11)	−0.0024 (8)	0.0024 (10)
C9	0.0343 (11)	0.0623 (18)	0.0332 (11)	−0.0013 (13)	0.0017 (8)	−0.0030 (12)
C10	0.0445 (11)	0.0562 (17)	0.0287 (10)	−0.0002 (13)	0.0029 (9)	−0.0030 (12)
C11	0.0433 (11)	0.0361 (13)	0.0265 (9)	0.0008 (11)	−0.0063 (9)	0.0000 (10)
C12	0.0344 (11)	0.0498 (15)	0.0340 (11)	−0.0006 (12)	−0.0028 (7)	−0.0015 (11)
C13	0.0362 (10)	0.0536 (16)	0.0275 (9)	0.0029 (12)	0.0012 (9)	−0.0020 (11)
S14	0.0511 (4)	0.0397 (4)	0.0303 (3)	0.0031 (3)	−0.0112 (3)	−0.0017 (3)
O15	0.0752 (17)	0.0556 (13)	0.0323 (10)	−0.0021 (11)	−0.0090 (10)	0.0044 (9)
O16	0.0520 (14)	0.0792 (17)	0.0511 (13)	0.0129 (12)	−0.0170 (10)	−0.0125 (12)
C17	0.079 (2)	0.0413 (16)	0.0475 (17)	−0.0046 (16)	−0.0150 (16)	−0.0061 (13)
C18	0.0574 (13)	0.0586 (10)	0.0219 (11)	−0.0071 (8)	−0.0054 (11)	−0.0009 (10)
C19	0.0624 (12)	0.0506 (8)	0.0553 (13)	−0.0060 (7)	0.0005 (11)	0.0047 (10)
C20	0.1038 (19)	0.0502 (9)	0.0672 (16)	−0.0124 (8)	−0.0070 (15)	0.0043 (12)
C21	0.108 (2)	0.0372 (13)	0.072 (2)	−0.0143 (9)	−0.014 (2)	−0.0031 (16)
C22	0.1038 (19)	0.0502 (9)	0.0672 (16)	−0.0124 (8)	−0.0070 (15)	0.0043 (12)
C23	0.0624 (12)	0.0506 (8)	0.0553 (13)	−0.0060 (7)	0.0005 (11)	0.0047 (10)
C24	0.0382 (15)	0.0485 (15)	0.0255 (9)	0.0072 (12)	−0.0003 (10)	0.0026 (10)
O25	0.0392 (11)	0.0568 (12)	0.0298 (9)	0.0082 (9)	0.0036 (8)	0.0102 (8)
C26	0.0405 (12)	0.0352 (13)	0.0298 (11)	−0.0026 (10)	0.0013 (9)	0.0000 (9)
C27	0.0380 (11)	0.0400 (14)	0.0392 (11)	−0.0019 (10)	−0.0038 (10)	0.0033 (10)
C28	0.0343 (13)	0.0546 (17)	0.0455 (13)	−0.0032 (11)	0.0039 (9)	0.0006 (12)
C29	0.0428 (12)	0.0581 (18)	0.0385 (12)	−0.0055 (12)	0.0077 (9)	0.0068 (11)
C30	0.0410 (11)	0.0399 (14)	0.0316 (9)	−0.0061 (10)	0.0006 (8)	0.0012 (9)
C31	0.0368 (12)	0.0420 (14)	0.0298 (10)	−0.0003 (10)	0.0007 (8)	0.0007 (9)
F32	0.0378 (11)	0.1016 (17)	0.0649 (12)	0.0112 (10)	0.0123 (9)	0.0152 (11)
C33	0.0487 (13)	0.0452 (15)	0.0307 (9)	−0.0077 (11)	−0.0005 (9)	0.0043 (8)
C34	0.0585 (17)	0.077 (2)	0.0420 (15)	0.0160 (15)	0.0030 (12)	0.0200 (14)
C35	0.081 (3)	0.116 (4)	0.052 (2)	0.034 (2)	−0.0026 (19)	0.030 (2)
O36	0.0638 (18)	0.134 (3)	0.0560 (16)	−0.0041 (17)	−0.0201 (13)	0.0216 (17)
C37	0.078 (3)	0.098 (3)	0.0351 (14)	−0.009 (2)	−0.0121 (15)	0.0027 (16)
C38	0.066 (2)	0.064 (2)	0.0346 (11)	−0.0127 (15)	−0.0055 (11)	−0.0046 (11)
O39	0.0774 (17)	0.0554 (13)	0.0425 (12)	−0.0217 (12)	−0.0081 (11)	0.0133 (10)
C40	0.166 (5)	0.058 (2)	0.077 (3)	−0.039 (3)	−0.029 (3)	0.000 (2)

Geometric parameters (Å, º)

N4—C8	1.394 (3)	C21—C22	1.357 (6)
N4—C3	1.463 (4)	C21—H21	0.9300
N4—C5	1.488 (3)	C22—C23	1.407 (5)
C5—C18	1.521 (4)	C22—H22	0.9300
C5—C6	1.540 (3)	C23—H23	0.9300
C5—H5	0.9800	C24—O25	1.418 (3)
C6—O1	1.418 (3)	C24—H24A	0.9700
C6—C24	1.513 (4)	C24—H24B	0.9700
C6—H6	0.9800	O25—C26	1.368 (3)
O1—C2	1.425 (3)	C26—C27	1.388 (4)
C3—C2	1.510 (4)	C26—C31	1.393 (4)
C3—H3A	0.9700	C27—C28	1.381 (4)
C3—H3B	0.9700	C27—H27	0.9300
C2—O7	1.363 (4)	C28—C29	1.367 (4)
C2—H2	0.9800	C28—F32	1.369 (3)
O7—H7	0.8200	C29—C30	1.393 (4)
C8—C13	1.401 (4)	C29—H29	0.9300
C8—C9	1.402 (4)	C30—C31	1.394 (4)
C9—C10	1.381 (4)	C30—C33	1.526 (4)
C9—H9	0.9300	C31—H31	0.9300
C10—C11	1.381 (4)	C33—O39	1.443 (4)
C10—H10	0.9300	C33—C34	1.522 (5)
C11—C12	1.384 (4)	C33—C38	1.527 (4)
C11—S14	1.751 (3)	C34—C35	1.528 (4)
C12—C13	1.377 (4)	C34—H34A	0.9700
C12—H12	0.9300	C34—H34B	0.9700
C13—H13	0.9300	C35—O36	1.416 (6)
S14—O16	1.435 (3)	C35—H35A	0.9700
S14—O15	1.441 (2)	C35—H35B	0.9700
S14—C17	1.751 (3)	O36—C37	1.424 (5)
C17—H17A	0.9600	C37—C38	1.509 (5)
C17—H17B	0.9600	C37—H37A	0.9700
C17—H17C	0.9600	C37—H37B	0.9700
C18—C19	1.387 (5)	C38—H38A	0.9700
C18—C23	1.390 (5)	C38—H38B	0.9700
C19—C20	1.387 (5)	O39—C40	1.413 (5)
C19—H19	0.9300	C40—H40A	0.9600
C20—C21	1.361 (6)	C40—H40B	0.9600
C20—H20	0.9300	C40—H40C	0.9600
C8—N4—C3	117.7 (2)	C20—C21—H21	119.6
C8—N4—C5	117.1 (2)	C21—C22—C23	120.3 (4)
C3—N4—C5	118.0 (2)	C21—C22—H22	119.8
N4—C5—C18	113.0 (2)	C23—C22—H22	119.8
N4—C5—C6	108.8 (2)	C18—C23—C22	119.4 (4)
C18—C5—C6	114.5 (2)	C18—C23—H23	120.3
N4—C5—H5	106.7	C22—C23—H23	120.3
C18—C5—H5	106.7	O25—C24—C6	108.0 (2)
C6—C5—H5	106.7	O25—C24—H24A	110.1
O1—C6—C24	104.9 (2)	C6—C24—H24A	110.1
O1—C6—C5	111.6 (2)	O25—C24—H24B	110.1
C24—C6—C5	113.9 (2)	C6—C24—H24B	110.1
O1—C6—H6	108.7	H24A—C24—H24B	108.4
C24—C6—H6	108.7	C26—O25—C24	117.6 (2)
C5—C6—H6	108.7	O25—C26—C27	114.3 (2)
C6—O1—C2	109.56 (19)	O25—C26—C31	124.4 (3)
N4—C3—C2	111.6 (2)	C27—C26—C31	121.4 (2)
N4—C3—H3A	109.3	C28—C27—C26	116.3 (3)
C2—C3—H3A	109.3	C28—C27—H27	121.9
N4—C3—H3B	109.3	C26—C27—H27	121.9
C2—C3—H3B	109.3	C29—C28—F32	118.5 (3)
H3A—C3—H3B	108.0	C29—C28—C27	124.4 (3)
O7—C2—O1	108.3 (2)	F32—C28—C27	117.1 (3)
O7—C2—C3	108.3 (2)	C28—C29—C30	118.7 (3)
O1—C2—C3	109.9 (2)	C28—C29—H29	120.7
O7—C2—H2	110.1	C30—C29—H29	120.7
O1—C2—H2	110.1	C29—C30—C31	119.0 (3)
C3—C2—H2	110.1	C29—C30—C33	118.4 (2)
C2—O7—H7	109.5	C31—C30—C33	122.6 (3)
N4—C8—C13	120.3 (2)	C26—C31—C30	120.2 (3)
N4—C8—C9	122.1 (2)	C26—C31—H31	119.9
C13—C8—C9	117.6 (2)	C30—C31—H31	119.9
C10—C9—C8	121.3 (3)	O39—C33—C34	110.6 (3)
C10—C9—H9	119.3	O39—C33—C30	108.4 (2)
C8—C9—H9	119.3	C34—C33—C30	114.4 (2)
C9—C10—C11	119.9 (3)	O39—C33—C38	104.0 (2)
C9—C10—H10	120.0	C34—C33—C38	107.9 (3)
C11—C10—H10	120.0	C30—C33—C38	111.2 (3)
C10—C11—C12	119.8 (2)	C33—C34—C35	110.8 (3)
C10—C11—S14	121.1 (2)	C33—C34—H34A	109.5
C12—C11—S14	119.1 (2)	C35—C34—H34A	109.5
C13—C12—C11	120.6 (3)	C33—C34—H34B	109.5
C13—C12—H12	119.7	C35—C34—H34B	109.5
C11—C12—H12	119.7	H34A—C34—H34B	108.1
C12—C13—C8	120.8 (3)	O36—C35—C34	111.6 (4)
C12—C13—H13	119.6	O36—C35—H35A	109.3
C8—C13—H13	119.6	C34—C35—H35A	109.3
O16—S14—O15	118.05 (15)	O36—C35—H35B	109.3
O16—S14—C11	109.06 (14)	C34—C35—H35B	109.3
O15—S14—C11	108.15 (13)	H35A—C35—H35B	108.0
O16—S14—C17	108.30 (18)	C35—O36—C37	110.5 (3)
O15—S14—C17	106.49 (16)	O36—C37—C38	112.3 (3)
C11—S14—C17	106.16 (14)	O36—C37—H37A	109.1
S14—C17—H17A	109.5	C38—C37—H37A	109.1
S14—C17—H17B	109.5	O36—C37—H37B	109.1
H17A—C17—H17B	109.5	C38—C37—H37B	109.1
S14—C17—H17C	109.5	H37A—C37—H37B	107.9
H17A—C17—H17C	109.5	C37—C38—C33	112.7 (3)
H17B—C17—H17C	109.5	C37—C38—H38A	109.0
C19—C18—C23	118.7 (3)	C33—C38—H38A	109.0
C19—C18—C5	122.7 (3)	C37—C38—H38B	109.0
C23—C18—C5	118.6 (3)	C33—C38—H38B	109.0
C20—C19—C18	120.8 (4)	H38A—C38—H38B	107.8
C20—C19—H19	119.6	C40—O39—C33	115.5 (3)
C18—C19—H19	119.6	O39—C40—H40A	109.5
C21—C20—C19	119.8 (4)	O39—C40—H40B	109.5
C21—C20—H20	120.1	H40A—C40—H40B	109.5
C19—C20—H20	120.1	O39—C40—H40C	109.5
C22—C21—C20	120.8 (4)	H40A—C40—H40C	109.5
C22—C21—H21	119.6	H40B—C40—H40C	109.5
C8—N4—C5—C18	61.5 (3)	C18—C19—C20—C21	1.3 (6)
C3—N4—C5—C18	−88.1 (3)	C19—C20—C21—C22	−2.0 (6)
C8—N4—C5—C6	−170.1 (2)	C20—C21—C22—C23	0.6 (6)
C3—N4—C5—C6	40.2 (3)	C19—C18—C23—C22	−2.3 (5)
N4—C5—C6—O1	−50.9 (3)	C5—C18—C23—C22	178.3 (3)
C18—C5—C6—O1	76.6 (3)	C21—C22—C23—C18	1.6 (6)
N4—C5—C6—C24	−169.5 (2)	O1—C6—C24—O25	178.3 (2)
C18—C5—C6—C24	−42.0 (3)	C5—C6—C24—O25	−59.4 (3)
C24—C6—O1—C2	−170.2 (2)	C6—C24—O25—C26	−176.7 (2)
C5—C6—O1—C2	65.9 (3)	C24—O25—C26—C27	173.6 (2)
C8—N4—C3—C2	168.5 (2)	C24—O25—C26—C31	−6.1 (4)
C5—N4—C3—C2	−42.0 (4)	O25—C26—C27—C28	−177.9 (3)
C6—O1—C2—O7	176.2 (2)	C31—C26—C27—C28	1.8 (4)
C6—O1—C2—C3	−65.6 (3)	C26—C27—C28—C29	−1.6 (5)
N4—C3—C2—O7	170.6 (2)	C26—C27—C28—F32	177.3 (3)
N4—C3—C2—O1	52.4 (3)	F32—C28—C29—C30	−179.3 (3)
C3—N4—C8—C13	−177.3 (3)	C27—C28—C29—C30	−0.4 (5)
C5—N4—C8—C13	32.9 (4)	C28—C29—C30—C31	2.3 (4)
C3—N4—C8—C9	0.7 (4)	C28—C29—C30—C33	−177.1 (3)
C5—N4—C8—C9	−149.1 (3)	O25—C26—C31—C30	179.6 (3)
N4—C8—C9—C10	−179.9 (3)	C27—C26—C31—C30	0.0 (4)
C13—C8—C9—C10	−1.8 (4)	C29—C30—C31—C26	−2.1 (4)
C8—C9—C10—C11	0.5 (5)	C33—C30—C31—C26	177.3 (2)
C9—C10—C11—C12	1.0 (4)	C29—C30—C33—O39	50.8 (3)
C9—C10—C11—S14	179.8 (2)	C31—C30—C33—O39	−128.5 (3)
C10—C11—C12—C13	−1.2 (4)	C29—C30—C33—C34	174.7 (3)
S14—C11—C12—C13	−180.0 (2)	C31—C30—C33—C34	−4.7 (4)
C11—C12—C13—C8	−0.2 (5)	C29—C30—C33—C38	−62.9 (3)
N4—C8—C13—C12	179.7 (3)	C31—C30—C33—C38	117.7 (3)
C9—C8—C13—C12	1.6 (4)	O39—C33—C34—C35	−61.3 (4)
C10—C11—S14—O16	−161.4 (2)	C30—C33—C34—C35	176.0 (3)
C12—C11—S14—O16	17.3 (3)	C38—C33—C34—C35	51.8 (4)
C10—C11—S14—O15	−31.9 (3)	C33—C34—C35—O36	−59.1 (5)
C12—C11—S14—O15	146.9 (2)	C34—C35—O36—C37	61.2 (5)
C10—C11—S14—C17	82.1 (3)	C35—O36—C37—C38	−58.9 (4)
C12—C11—S14—C17	−99.2 (3)	O36—C37—C38—C33	54.8 (4)
N4—C5—C18—C19	58.1 (3)	O39—C33—C38—C37	67.1 (4)
C6—C5—C18—C19	−67.3 (3)	C34—C33—C38—C37	−50.4 (4)
N4—C5—C18—C23	−122.6 (3)	C30—C33—C38—C37	−176.5 (3)
C6—C5—C18—C23	112.0 (3)	C34—C33—O39—C40	−64.2 (4)
C23—C18—C19—C20	0.9 (5)	C30—C33—O39—C40	61.9 (4)
C5—C18—C19—C20	−179.7 (3)	C38—C33—O39—C40	−179.7 (4)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O7—H7···O15^i	0.82	1.96	2.736 (3)	157
C5—H5···O7^ii	0.98	2.38	3.358 (4)	177
C12—H12···O16	0.93	2.55	2.922 (4)	105
C13—H13···O7^ii	0.93	2.37	3.283 (3)	168
C17—H17A···O39^iii	0.96	2.46	3.406 (3)	167
C17—H17C···O36^iv	0.96	2.44	3.326 (4)	152
C34—H34A···F32^v	0.97	2.52	3.470 (4)	166

Symmetry codes: (i) x+1, −y+1/2, z+1/2; (ii) x−1, y, z; (iii) −x+1, −y, −z+1; (iv) x−1, y, z−1; (v) x+1, y, z.