Two androsterone derivatives as inhibitors of androgen biosynthesis

The title compounds, (3R,5S,5'R,8R,9S,10S,13S,14S)-10,13-dimethyl-5'-(2-methyl­prop­yl)tetra­deca­hydro-6'H-spiro­[cyclo­penta­[a]phenanthrene-3,2'-[1,4]oxazinane]-6',17(2H)-dione, C₂₆H₄₁NO₃, (I), and methyl (2R)-2-[(3R,5S,8R,9S,10S,13S,14S)-10,13-dimethyl-2',17-dioxohexa­deca­hydro-3'H-spiro­[cyclo­penta­[a]phenanthrene-3,5'-[1,3]oxazolidin-3'-yl]]-4-methyl­penta­noate, C₂₈H₄₃NO₅, (II), possess the typical steroid shape (A-D rings), but they differ in their extra E ring. The aza­lactone E ring in (I) shows a half-chair conformation, while the carbamate E ring of (II) is planar. The orientation of the E-ring substituent is clearly established and allows a rationalization of the biological results obtained with such androsterone derivatives.

S1. Comment

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) is an enzyme that catalyses the reduction of 4-androstene-3,17-dione into androgen testosterone (Poirier, 2010; Mohler et al., 2007; Maltais et al., 2011). This latter steroid hormone, as well as its natural metabolite dehydrotestosterone, is known to stimulate the proliferation of prostate cancer cells; the Scheme shows the biosynthesis of the androgenic hormone testosterone and a representation of azalactones (I) and (III) and carbamates (II) and (IV) tested as inhibitors of 17β-HSD3 (Inh = inhibition) (Poirier, 2008). Since 17β-HSD3 contributes to the production of androgens in men, inhibiting this enzyme is an interesting strategy to block androgen biosynthesis and to treat prostate cancer. Androsterone (ADT) derivatives substituted at position C-3 [C3?] were previously reported as inhibitors of 17β-HSD3 and it was established that a hydrophobic group is required to obtain good inhibition of 17β-HSD3 (Maltais et al., 2002), a β-oriented group producing a better inhibition than the α-oriented group (Tchedam-Ngatcha et al., 2005).

In our synthetic search for inhibitors of 17β-HSD3, we recently focused on the preparation of new ADT derivatives having an extra azalactone or carbamate E ring. For a better understanding of the structure–activity relationship (SAR) of these new inhibitors, especially the side-chain orientation, we analyzed the structures of the representative compounds (I) and (II) (see Scheme and Fig. 1).

The two compounds show fixed conformations of their extended side chains; no disorder is apparent in the structure analyses. Packing diagrams with van der Waals radii give the impression that these structures are not very tightly packed, in agreement with the low densities [1.162 Mg m^-3 in (I) and 1.200 Mg m^-3 in (II)]. The packing appears to be efficient enough, however, to be linked to the appearance of just one conformation of the side chain in each case.

The correct enantiomers, already known from the starting materials, were checked against the absolute structure parameters (Flack, 1983). For compound (I), the absolute structure parameter was found to be 0.12 (18) for 1747 Friedel pairs (83% Friedel coverage). For compound (II), it was 0.06 (18) for 2090 (100%) Friedel pairs. These two values are better than might have been expected considering that the highest anomalous contribution comes from oxygen atoms (Flack & Bernardinelli, 2008). A Bayesian statistics analysis on Bijvoet differences was also performed using the program PLATON (Spek, 2009). The Hooft parameters obtained (Hooft et al., 2008), -0.04 (7) and -0.05 (6) for compounds (I) and (II), respectively, are also in very good agreement with the known molecular absolute configurations, and were perhaps influenced positively by the use of copper radiation. Probability levels of having a false attribution, P3(false), are essentially zero for both compounds.

The steroid six-membered A, B and C rings appear as the well known fused-ring system, all in chair conformation, while the five-membered D ring is in a slightly twisted envelope conformation in both azalactone (I) and carbamate (II) (Yan et al., 2009) (Fig. 2). The heterocyclic ring of (I) is a half-chair perpendicular to the steroid backbone, while the heterocyclic ring of carbamate (II) is almost planar [maximum deviation?] and is perpendicular to the steroidal plane (Fig. 3). These extra heterocyclic E rings provide a restricted orientation to the isobutyl group in the azalactones (I) and (III) (see Scheme). In carbamates (II) and (IV), the methyl pentanoate group has a higher degree of liberty due to the free rotation around the exocyclic bond to the BN atom. In azalactone (I), the hydrophobic side chain has a distal orientation with respect to the longitudinal axis of the four-ring steroid system (to the right in Fig. 4a). Consequently, the isobutyl group of the other isomer, the azalactone (III), would be oriented to the left in a similar drawing, or in other words in a proximal disposition to the centerline of the four-ring system. Since the present compound (I) is a less potent inhibitor than its stereoisomer (III), it appears that the side chain must be proximal (on the left side in Fig. 4a) for better enzyme inhibition. The isobutyl group would thus point toward a hypothetical hydrophobic pocket of 17β-HSD3, which was previously deduced from SAR studies (Tchedam-Ngatcha et al., 2005; Maltais et al., 2011) but not confirmed because this membrane enzyme was never crystallized. In the case of carbamates (II) (Fig. 4b) and (IV), the inhibitory activity is the same (55 and 58% of inhibition at 0.1 µM) for both compounds due to the free rotation of the methyl pentanoate group, which promotes interaction with a hydrophobic pocket of the enzyme.

Related literature

For related literature, see: Flack (1983); Flack & Bernardinelli (2008); Hooft et al. (2008); Maltais et al. (2002, 2011); Mohler et al. (2007); Poirier (2008, 2010); Rouillard et al. (2008); Spek (2009); Tchedam-Ngatcha, Luu-The, Labrie & Poirier (2005); Yan et al. (2009).

S2. Experimental

Compounds (I) and (III) were synthesized by modification of an approach developed in our laboratory (Rouillard et al., 2008). Briefly, aminolysis of the oxirane at C-3 of androsterone with L and D-isoleucine methyl esters provided the corresponding amino alcohols, which were treated with sodium methoxide to afford azalactones (I) and (III). Compounds (II) and (IV) were prepared according to the method of Maltais et al. (2002) by treatment of each amino alcohol with triphosgene. X-ray-quality crystals of (I) and (II) were obtained by slow diffusion of hexane into a methylene chloride solution of the compound (hexane–methylene chloride 1:1 v/v) followed by slow evaporation.

S3. Refinement

H atoms were treated as riding, with C—H = 1.00 (methyl), 0.99 (methylene) and 0.98 Å (remainding H atoms), and with U_iso(H) = 1.5U_eq(C) for methyl H atoms and 1.2U_eq(C) otherwise. The N-bound H atom of (I) was located by difference Fourier synthesis; its coordinates were refined and its U_iso(H) value was constrained to 1.2U_eq(N).

Computing details

Data collection: APEX2 [or SMART?] (Bruker, 2011) for (I); APEX2 (Bruker, 2011) for (II). For both compounds, cell refinement: SAINT (Bruker, 2011); data reduction: XPREP (Bruker, 2008); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: UdMX (Maris, 2004).

Figures

	Fig. 1. The molecular structures of (a) azalactone (I) and (b) carbamate (II) with non-H atoms represented by their 50% probability ellipsoids.
	Fig. 2. The structures of (a) (I) and (b) (II), showing the conformations of the steroid A, B, C and D rings.
	Fig. 3. The E-ring conformations in (a) (I) and (b) (II).
	Fig. 4. The E-ring substituent conformation in (a) azalactone (I) and (b) carbamate (II). The isobutyl group of (I) is oriented away from the longitudinal axis of the steroid ring system, while the methyl pentanoate group of (II) has free rotation.

(I) (3R,5S,5'R,8R,9S,10S,13S, 14S)-10,13-dimethyl-5'-(2-methylpropyl)tetradecahydro-6'H- spiro[cyclopenta[a]phenanthrene-3,2'-[1,4]oxazinane]-6',17(2H)- dione

Crystal data

C26H41NO3	F(000) = 456
Mr = 415.60	Dx = 1.162 Mg m^−3
Monoclinic, P21	Cu Kα radiation, λ = 1.54178 Å
Hall symbol: P 2yb	Cell parameters from 9878 reflections
a = 13.07929 (17) Å	θ = 2.8–72.3°
b = 5.82873 (8) Å	µ = 0.58 mm^−1
c = 16.3140 (2) Å	T = 150 K
β = 107.3095 (6)°	Plate, colorless
V = 1187.37 (3) Å^3	0.25 × 0.11 × 0.05 mm
Z = 2

Data collection

Bruker SMART 6000 diffractometer	4334 independent reflections
Radiation source: Rotating Anode	4159 reflections with I > 2σ(I)
Helios optics monochromator	Rint = 0.038
Detector resolution: 5.5 pixels mm^-1	θmax = 72.5°, θmin = 2.8°
ω scans	h = −16→16
Absorption correction: multi-scan (SADABS; Sheldrick, 2008)	k = −6→7
Tmin = 0.810, Tmax = 0.971	l = −20→20
36176 measured reflections

Refinement

Refinement on F^2	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F^2 > 2σ(F^2)] = 0.040	w = 1/[σ^2(Fo^2) + (0.0735P)^2 + 0.0832P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.107	(Δ/σ)max = 0.001
S = 1.07	Δρmax = 0.18 e Å^−3
4334 reflections	Δρmin = −0.22 e Å^−3
279 parameters	Extinction correction: SHELXL97 (Sheldrick, 2008), Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
1 restraint	Extinction coefficient: 0.0046 (6)
Primary atom site location: structure-invariant direct methods	Absolute structure: Flack (1983), 1733 Friedel pairs
Secondary atom site location: difference Fourier map	Absolute structure parameter: 0.12 (18)

Special details

Experimental. X-ray crystallographic data for II were collected from a single-crystal sample, which was mounted on a loop fiber. Data were collected using a Bruker Platform diffractometer, equipped with a Bruker SMART 4 K Charged-Coupled Device (CCD) Area Detector using the program APEX2 and a Nonius FR591 rotating anode equiped with a Helios optics The crystal-to-detector distance was 5.0 cm, and the data collection was carried out in 512 x 512 pixel mode. The initial unit-cell parameters were determined by a least-squares fit of the angular setting of strong reflections, collected by a 10.0 degree scan in 33 frames over four different parts of the reciprocal space (132 frames total). One complete sphere of data was collected, to better than 0.80 Å resolution.

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
O3	0.52314 (8)	0.07663 (19)	0.32235 (6)	0.0379 (2)
O17	0.06829 (11)	−0.1106 (3)	−0.25496 (8)	0.0586 (3)
O22	0.66845 (9)	−0.1271 (2)	0.37364 (8)	0.0487 (3)
N20	0.59879 (10)	0.4242 (2)	0.44884 (8)	0.0398 (3)
H20	0.6198 (15)	0.526 (4)	0.4163 (12)	0.048*
C1	0.29683 (11)	0.0893 (3)	0.21029 (9)	0.0339 (3)
H1A	0.2221	0.0367	0.2002	0.041*
H1B	0.3396	−0.0438	0.2018	0.041*
C2	0.34086 (11)	0.1731 (3)	0.30308 (9)	0.0373 (3)
H2A	0.2920	0.2915	0.3136	0.045*
H2B	0.3415	0.0430	0.3422	0.045*
C3	0.45313 (11)	0.2730 (3)	0.32467 (8)	0.0329 (3)
C4	0.46339 (11)	0.4434 (3)	0.25645 (8)	0.0321 (3)
H4A	0.5401	0.4805	0.2668	0.039*
H4B	0.4260	0.5871	0.2627	0.039*
C5	0.41735 (10)	0.3551 (2)	0.16430 (8)	0.0281 (3)
H5	0.4600	0.2164	0.1591	0.034*
C6	0.43276 (11)	0.5300 (3)	0.09925 (8)	0.0339 (3)
H6A	0.5094	0.5719	0.1138	0.041*
H6B	0.3917	0.6707	0.1024	0.041*
C7	0.39531 (10)	0.4339 (3)	0.00793 (8)	0.0337 (3)
H7A	0.4433	0.3068	0.0029	0.040*
H7B	0.4006	0.5556	−0.0330	0.040*
C8	0.27975 (10)	0.3456 (2)	−0.01628 (8)	0.0279 (3)
H8	0.2310	0.4793	−0.0187	0.033*
C9	0.26458 (10)	0.1737 (2)	0.05167 (8)	0.0274 (3)
H9	0.3143	0.0429	0.0524	0.033*
C10	0.29910 (10)	0.2763 (2)	0.14390 (8)	0.0280 (3)
C11	0.15039 (11)	0.0715 (3)	0.02490 (9)	0.0338 (3)
H11A	0.1461	−0.0484	0.0667	0.041*
H11B	0.0987	0.1938	0.0270	0.041*
C12	0.11827 (11)	−0.0331 (3)	−0.06529 (9)	0.0366 (3)
H12A	0.1637	−0.1685	−0.0660	0.044*
H12B	0.0428	−0.0849	−0.0808	0.044*
C13	0.13103 (10)	0.1415 (3)	−0.13083 (9)	0.0324 (3)
C14	0.24756 (11)	0.2288 (3)	−0.10365 (8)	0.0318 (3)
H14	0.2938	0.0893	−0.0973	0.038*
C15	0.25711 (12)	0.3548 (3)	−0.18407 (9)	0.0426 (4)
H15A	0.3328	0.3697	−0.1832	0.051*
H15B	0.2242	0.5092	−0.1893	0.051*
C16	0.19432 (14)	0.1950 (4)	−0.25711 (10)	0.0562 (5)
H16A	0.1513	0.2860	−0.3067	0.067*
H16B	0.2441	0.0957	−0.2765	0.067*
C17	0.12173 (12)	0.0507 (3)	−0.22022 (9)	0.0424 (4)
C18	0.04720 (11)	0.3353 (3)	−0.14356 (9)	0.0362 (3)
H18A	0.0570	0.4446	−0.1863	0.054*
H18B	0.0564	0.4147	−0.0889	0.054*
H18C	−0.0249	0.2696	−0.1636	0.054*
C19	0.22363 (11)	0.4728 (3)	0.15140 (9)	0.0354 (3)
H19A	0.1533	0.4097	0.1489	0.053*
H19B	0.2159	0.5809	0.1039	0.053*
H19C	0.2537	0.5528	0.2061	0.053*
C20	0.48529 (12)	0.3760 (3)	0.41440 (9)	0.0389 (3)
H20A	0.4450	0.5204	0.4131	0.047*
H20B	0.4643	0.2687	0.4536	0.047*
C21	0.66213 (12)	0.2164 (3)	0.45255 (9)	0.0391 (4)
H21	0.6612	0.1343	0.5062	0.047*
C22	0.61980 (11)	0.0455 (3)	0.37897 (9)	0.0353 (3)
C23	0.77868 (13)	0.2790 (4)	0.46404 (10)	0.0470 (4)
H23A	0.7828	0.3710	0.4141	0.056*
H23B	0.8203	0.1365	0.4652	0.056*
C24	0.82962 (15)	0.4159 (5)	0.54688 (12)	0.0627 (6)
H24	0.7791	0.5428	0.5492	0.075*
C25	0.8442 (2)	0.2714 (6)	0.62589 (13)	0.0866 (9)
H25A	0.7740	0.2219	0.6294	0.130*
H25B	0.8805	0.3616	0.6769	0.130*
H25C	0.8875	0.1364	0.6228	0.130*
C26	0.9336 (3)	0.5256 (9)	0.5437 (2)	0.1324 (16)
H26A	0.9630	0.6198	0.5951	0.199*
H26B	0.9199	0.6225	0.4924	0.199*
H26C	0.9852	0.4055	0.5415	0.199*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O3	0.0412 (5)	0.0341 (6)	0.0350 (5)	0.0077 (4)	0.0063 (4)	−0.0024 (4)
O17	0.0693 (8)	0.0492 (8)	0.0478 (6)	−0.0078 (7)	0.0028 (6)	−0.0149 (6)
O22	0.0442 (6)	0.0391 (6)	0.0605 (7)	0.0104 (5)	0.0119 (5)	0.0008 (5)
N20	0.0463 (7)	0.0404 (8)	0.0307 (6)	0.0008 (6)	0.0082 (5)	−0.0046 (5)
C1	0.0347 (6)	0.0335 (8)	0.0336 (7)	−0.0022 (6)	0.0102 (5)	0.0044 (6)
C2	0.0400 (7)	0.0408 (9)	0.0330 (7)	−0.0005 (7)	0.0136 (6)	0.0060 (6)
C3	0.0366 (6)	0.0321 (8)	0.0293 (6)	0.0052 (6)	0.0087 (5)	−0.0007 (6)
C4	0.0333 (6)	0.0311 (8)	0.0308 (6)	−0.0016 (6)	0.0078 (5)	−0.0018 (6)
C5	0.0268 (6)	0.0269 (7)	0.0300 (6)	−0.0004 (5)	0.0075 (5)	−0.0012 (5)
C6	0.0340 (6)	0.0344 (8)	0.0331 (6)	−0.0081 (6)	0.0094 (5)	0.0009 (6)
C7	0.0307 (6)	0.0404 (9)	0.0303 (6)	−0.0048 (6)	0.0094 (5)	0.0019 (6)
C8	0.0272 (6)	0.0269 (7)	0.0297 (6)	0.0005 (5)	0.0086 (5)	0.0016 (5)
C9	0.0262 (6)	0.0231 (6)	0.0316 (6)	0.0017 (5)	0.0066 (5)	0.0016 (5)
C10	0.0278 (6)	0.0261 (7)	0.0305 (6)	0.0006 (5)	0.0094 (5)	0.0020 (5)
C11	0.0315 (6)	0.0306 (8)	0.0376 (7)	−0.0054 (5)	0.0076 (5)	0.0047 (6)
C12	0.0338 (6)	0.0280 (7)	0.0422 (7)	−0.0048 (6)	0.0025 (5)	0.0012 (6)
C13	0.0309 (6)	0.0294 (8)	0.0335 (7)	−0.0005 (6)	0.0042 (5)	−0.0019 (6)
C14	0.0307 (6)	0.0315 (8)	0.0319 (7)	0.0013 (5)	0.0075 (5)	−0.0024 (5)
C15	0.0399 (7)	0.0570 (10)	0.0314 (7)	−0.0076 (7)	0.0110 (6)	−0.0003 (7)
C16	0.0538 (9)	0.0806 (14)	0.0337 (8)	−0.0127 (10)	0.0121 (7)	−0.0110 (8)
C17	0.0408 (7)	0.0434 (9)	0.0365 (7)	0.0029 (7)	0.0014 (6)	−0.0075 (7)
C18	0.0300 (6)	0.0350 (8)	0.0392 (7)	0.0012 (6)	0.0035 (5)	0.0032 (6)
C19	0.0352 (7)	0.0354 (8)	0.0354 (7)	0.0052 (6)	0.0102 (5)	−0.0031 (6)
C20	0.0452 (7)	0.0421 (9)	0.0297 (6)	0.0068 (7)	0.0115 (5)	−0.0022 (6)
C21	0.0405 (7)	0.0468 (10)	0.0294 (6)	0.0025 (6)	0.0093 (5)	0.0040 (6)
C22	0.0370 (6)	0.0343 (8)	0.0355 (6)	0.0023 (6)	0.0119 (5)	0.0071 (6)
C23	0.0427 (8)	0.0602 (11)	0.0390 (7)	−0.0065 (8)	0.0133 (6)	−0.0016 (8)
C24	0.0487 (9)	0.0815 (16)	0.0499 (9)	−0.0030 (10)	0.0022 (7)	−0.0153 (10)
C25	0.0881 (16)	0.114 (2)	0.0406 (10)	0.0264 (16)	−0.0076 (10)	−0.0063 (12)
C26	0.093 (2)	0.179 (4)	0.126 (3)	−0.074 (3)	0.0335 (18)	−0.075 (3)

Geometric parameters (Å, º)

O3—C22	1.3378 (17)	C12—C13	1.5210 (19)
O3—C3	1.4732 (17)	C12—H12a	0.9900
O17—C17	1.207 (2)	C12—H12b	0.9900
O22—C22	1.2070 (19)	C13—C17	1.5219 (19)
N20—C20	1.4499 (19)	C13—C14	1.5415 (18)
N20—C21	1.459 (2)	C13—C18	1.544 (2)
N20—H20	0.89 (2)	C14—C15	1.541 (2)
C1—C2	1.5306 (19)	C14—H14	1.0000
C1—C10	1.5430 (18)	C15—C16	1.543 (2)
C1—H1a	0.9900	C15—H15a	0.9900
C1—H1b	0.9900	C15—H15b	0.9900
C2—C3	1.5205 (19)	C16—C17	1.520 (3)
C2—H2a	0.9900	C16—H16a	0.9900
C2—H2b	0.9900	C16—H16b	0.9900
C3—C20	1.5214 (18)	C18—H18a	0.9800
C3—C4	1.5271 (19)	C18—H18b	0.9800
C4—C5	1.5325 (17)	C18—H18c	0.9800
C4—H4a	0.9900	C19—H19a	0.9800
C4—H4b	0.9900	C19—H19b	0.9800
C5—C6	1.5274 (18)	C19—H19c	0.9800
C5—C10	1.5516 (16)	C20—H20a	0.9900
C5—H5	1.0000	C20—H20b	0.9900
C6—C7	1.5292 (18)	C21—C23	1.524 (2)
C6—H6a	0.9900	C21—C22	1.531 (2)
C6—H6b	0.9900	C21—H21	1.0000
C7—C8	1.5330 (17)	C23—C24	1.540 (2)
C7—H7a	0.9900	C23—H23a	0.9900
C7—H7b	0.9900	C23—H23b	0.9900
C8—C14	1.5216 (17)	C24—C25	1.504 (3)
C8—C9	1.5502 (17)	C24—C26	1.518 (3)
C8—H8	1.0000	C24—H24	1.0000
C9—C11	1.5452 (17)	C25—H25a	0.9800
C9—C10	1.5560 (17)	C25—H25b	0.9800
C9—H9	1.0000	C25—H25c	0.9800
C10—C19	1.5405 (19)	C26—H26a	0.9800
C11—C12	1.5317 (19)	C26—H26b	0.9800
C11—H11a	0.9900	C26—H26c	0.9800
C11—H11b	0.9900
C22—O3—C3	123.68 (12)	C12—C13—C14	108.94 (11)
C20—N20—C21	111.01 (13)	C17—C13—C14	100.41 (10)
C20—N20—H20	111.1 (13)	C12—C13—C18	111.23 (11)
C21—N20—H20	107.7 (13)	C17—C13—C18	105.93 (12)
C2—C1—C10	112.87 (12)	C14—C13—C18	113.51 (12)
C2—C1—H1A	109.0	C8—C14—C15	120.96 (12)
C10—C1—H1A	109.0	C8—C14—C13	113.04 (11)
C2—C1—H1B	109.0	C15—C14—C13	103.66 (10)
C10—C1—H1B	109.0	C8—C14—H14	106.1
H1A—C1—H1B	107.8	C15—C14—H14	106.1
C3—C2—C1	113.86 (11)	C13—C14—H14	106.1
C3—C2—H2A	108.8	C14—C15—C16	102.14 (13)
C1—C2—H2A	108.8	C14—C15—H15A	111.3
C3—C2—H2B	108.8	C16—C15—H15A	111.3
C1—C2—H2B	108.8	C14—C15—H15B	111.3
H2A—C2—H2B	107.7	C16—C15—H15B	111.3
O3—C3—C2	105.15 (12)	H15A—C15—H15B	109.2
O3—C3—C20	109.60 (11)	C17—C16—C15	106.27 (12)
C2—C3—C20	110.21 (11)	C17—C16—H16A	110.5
O3—C3—C4	107.25 (10)	C15—C16—H16A	110.5
C2—C3—C4	111.62 (11)	C17—C16—H16B	110.5
C20—C3—C4	112.67 (13)	C15—C16—H16B	110.5
C3—C4—C5	113.72 (12)	H16A—C16—H16B	108.7
C3—C4—H4A	108.8	O17—C17—C16	125.98 (15)
C5—C4—H4A	108.8	O17—C17—C13	126.21 (16)
C3—C4—H4B	108.8	C16—C17—C13	107.79 (13)
C5—C4—H4B	108.8	C13—C18—H18A	109.5
H4A—C4—H4B	107.7	C13—C18—H18B	109.5
C6—C5—C4	111.27 (11)	H18A—C18—H18B	109.5
C6—C5—C10	112.19 (10)	C13—C18—H18C	109.5
C4—C5—C10	112.68 (10)	H18A—C18—H18C	109.5
C6—C5—H5	106.8	H18B—C18—H18C	109.5
C4—C5—H5	106.8	C10—C19—H19A	109.5
C10—C5—H5	106.8	C10—C19—H19B	109.5
C5—C6—C7	111.24 (12)	H19A—C19—H19B	109.5
C5—C6—H6A	109.4	C10—C19—H19C	109.5
C7—C6—H6A	109.4	H19A—C19—H19C	109.5
C5—C6—H6B	109.4	H19B—C19—H19C	109.5
C7—C6—H6B	109.4	N20—C20—C3	114.04 (11)
H6A—C6—H6B	108.0	N20—C20—H20A	108.7
C6—C7—C8	112.30 (10)	C3—C20—H20A	108.7
C6—C7—H7A	109.1	N20—C20—H20B	108.7
C8—C7—H7A	109.1	C3—C20—H20B	108.7
C6—C7—H7B	109.1	H20A—C20—H20B	107.6
C8—C7—H7B	109.1	N20—C21—C23	109.94 (14)
H7A—C7—H7B	107.9	N20—C21—C22	116.07 (12)
C14—C8—C7	111.62 (10)	C23—C21—C22	111.55 (13)
C14—C8—C9	108.79 (11)	N20—C21—H21	106.2
C7—C8—C9	111.03 (10)	C23—C21—H21	106.2
C14—C8—H8	108.4	C22—C21—H21	106.2
C7—C8—H8	108.4	O22—C22—O3	118.25 (15)
C9—C8—H8	108.4	O22—C22—C21	121.55 (13)
C11—C9—C8	111.45 (10)	O3—C22—C21	120.00 (13)
C11—C9—C10	113.54 (10)	C21—C23—C24	112.82 (13)
C8—C9—C10	112.40 (11)	C21—C23—H23A	109.0
C11—C9—H9	106.3	C24—C23—H23A	109.0
C8—C9—H9	106.3	C21—C23—H23B	109.0
C10—C9—H9	106.3	C24—C23—H23B	109.0
C19—C10—C1	108.83 (10)	H23A—C23—H23B	107.8
C19—C10—C5	112.60 (11)	C25—C24—C26	112.3 (2)
C1—C10—C5	106.54 (10)	C25—C24—C23	111.9 (2)
C19—C10—C9	110.74 (10)	C26—C24—C23	110.27 (17)
C1—C10—C9	110.29 (11)	C25—C24—H24	107.4
C5—C10—C9	107.77 (9)	C26—C24—H24	107.4
C12—C11—C9	113.00 (11)	C23—C24—H24	107.4
C12—C11—H11A	109.0	C24—C25—H25A	109.5
C9—C11—H11A	109.0	C24—C25—H25B	109.5
C12—C11—H11B	109.0	H25A—C25—H25B	109.5
C9—C11—H11B	109.0	C24—C25—H25C	109.5
H11A—C11—H11B	107.8	H25A—C25—H25C	109.5
C13—C12—C11	110.65 (12)	H25B—C25—H25C	109.5
C13—C12—H12A	109.5	C24—C26—H26A	109.5
C11—C12—H12A	109.5	C24—C26—H26B	109.5
C13—C12—H12B	109.5	H26A—C26—H26B	109.5
C11—C12—H12B	109.5	C24—C26—H26C	109.5
H12A—C12—H12B	108.1	H26A—C26—H26C	109.5
C12—C13—C17	116.52 (13)	H26B—C26—H26C	109.5
C10—C1—C2—C3	−54.94 (16)	C11—C12—C13—C14	56.60 (15)
C22—O3—C3—C2	−139.66 (13)	C11—C12—C13—C18	−69.26 (14)
C22—O3—C3—C20	−21.20 (18)	C7—C8—C14—C15	−55.32 (17)
C22—O3—C3—C4	101.41 (14)	C9—C8—C14—C15	−178.18 (11)
C1—C2—C3—O3	−68.38 (15)	C7—C8—C14—C13	−178.98 (12)
C1—C2—C3—C20	173.58 (13)	C9—C8—C14—C13	58.16 (14)
C1—C2—C3—C4	47.58 (17)	C12—C13—C14—C8	−60.52 (15)
O3—C3—C4—C5	67.14 (14)	C17—C13—C14—C8	176.60 (12)
C2—C3—C4—C5	−47.53 (16)	C18—C13—C14—C8	64.00 (15)
C20—C3—C4—C5	−172.16 (11)	C12—C13—C14—C15	166.75 (12)
C3—C4—C5—C6	−178.40 (11)	C17—C13—C14—C15	43.86 (15)
C3—C4—C5—C10	54.59 (15)	C18—C13—C14—C15	−68.73 (14)
C4—C5—C6—C7	175.26 (11)	C8—C14—C15—C16	−168.26 (13)
C10—C5—C6—C7	−57.47 (15)	C13—C14—C15—C16	−40.28 (16)
C5—C6—C7—C8	54.05 (16)	C14—C15—C16—C17	20.65 (18)
C6—C7—C8—C14	−174.20 (12)	C15—C16—C17—O17	−171.87 (17)
C6—C7—C8—C9	−52.63 (16)	C15—C16—C17—C13	6.53 (19)
C14—C8—C9—C11	−53.05 (14)	C12—C13—C17—O17	30.2 (2)
C7—C8—C9—C11	−176.26 (11)	C14—C13—C17—O17	147.59 (16)
C14—C8—C9—C10	178.20 (10)	C18—C13—C17—O17	−94.10 (19)
C7—C8—C9—C10	54.99 (14)	C12—C13—C17—C16	−148.22 (14)
C2—C1—C10—C19	−64.18 (14)	C14—C13—C17—C16	−30.80 (16)
C2—C1—C10—C5	57.47 (14)	C18—C13—C17—C16	87.51 (15)
C2—C1—C10—C9	174.16 (10)	C21—N20—C20—C3	−58.68 (17)
C6—C5—C10—C19	−64.65 (14)	O3—C3—C20—N20	50.36 (17)
C4—C5—C10—C19	61.86 (14)	C2—C3—C20—N20	165.63 (13)
C6—C5—C10—C1	176.12 (11)	C4—C3—C20—N20	−68.97 (17)
C4—C5—C10—C1	−57.36 (14)	C20—N20—C21—C23	163.93 (11)
C6—C5—C10—C9	57.76 (14)	C20—N20—C21—C22	36.15 (16)
C4—C5—C10—C9	−175.72 (11)	C3—O3—C22—O22	176.53 (12)
C11—C9—C10—C19	−60.62 (14)	C3—O3—C22—C21	1.5 (2)
C8—C9—C10—C19	67.04 (13)	N20—C21—C22—O22	176.62 (14)
C11—C9—C10—C1	59.91 (14)	C23—C21—C22—O22	49.6 (2)
C8—C9—C10—C1	−172.44 (10)	N20—C21—C22—O3	−8.46 (19)
C11—C9—C10—C5	175.83 (11)	C23—C21—C22—O3	−135.45 (15)
C8—C9—C10—C5	−56.52 (13)	N20—C21—C23—C24	59.92 (19)
C8—C9—C11—C12	53.00 (16)	C22—C21—C23—C24	−169.84 (16)
C10—C9—C11—C12	−178.85 (11)	C21—C23—C24—C25	69.0 (2)
C9—C11—C12—C13	−54.84 (15)	C21—C23—C24—C26	−165.3 (3)
C11—C12—C13—C17	169.22 (11)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N20—H20···O22^i	0.89 (2)	2.29 (2)	3.1369 (19)	158.5 (17)

Symmetry code: (i) x, y+1, z.

(II) methyl (2R)-2-[(3R,5S,8R,9S,10S, 13S,14S)-10,13-dimethyl-2',17-dioxohexadecahydro-3'H- spiro[cyclopenta[a]phenanthrene-3,5'-[1,3]oxazolidin-3'-yl]]- 4-methylpentanoate

Crystal data

C28H43NO5	F(000) = 1032
Mr = 473.63	Dx = 1.200 Mg m^−3
Orthorhombic, P212121	Cu Kα radiation, λ = 1.54178 Å
Hall symbol: P 2ac 2ab	Cell parameters from 9843 reflections
a = 6.3941 (2) Å	θ = 3.1–69.5°
b = 18.1440 (7) Å	µ = 0.65 mm^−1
c = 22.6047 (9) Å	T = 150 K
V = 2622.47 (17) Å^3	Needle, colorless
Z = 4	0.12 × 0.05 × 0.05 mm

Data collection

Bruker Microstar diffractometer	4933 independent reflections
Radiation source: Rotating Anode	4697 reflections with I > 2σ(I)
Helios optics monochromator	Rint = 0.052
Detector resolution: 8.3 pixels mm^-1	θmax = 69.7°, θmin = 3.1°
ω scans	h = −7→6
Absorption correction: multi-scan (SADABS; Sheldrick, 2008)	k = −22→22
Tmin = 0.787, Tmax = 0.968	l = −27→27
43157 measured reflections

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.037	H-atom parameters constrained
wR(F^2) = 0.101	w = 1/[σ^2(Fo^2) + (0.0555P)^2 + 0.4002P] where P = (Fo^2 + 2Fc^2)/3
S = 1.06	(Δ/σ)max = 0.001
4933 reflections	Δρmax = 0.23 e Å^−3
312 parameters	Δρmin = −0.14 e Å^−3
0 restraints	Absolute structure: Flack (1983), 2087 Friedel pairs
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.06 (18)

Special details

Experimental. X-ray crystallographic data for I were collected from a single-crystal sample, which was mounted on a loop fiber. Data were collected using a Bruker microstar diffractometer equiped with a Platinum 135 CCD Detector, a Helios optics and a Kappa goniometer. The crystal-to-detector distance was 4.0 cm, and the data collection was carried out in 512 x 512 pixel mode. The initial unit-cell parameters were determined by a least-squares fit of the angular setting of strong reflections, collected by a 10.0 degree scan in 33 frames over three different parts of the reciprocal space (99 frames total).

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
O3	0.89616 (15)	0.90363 (6)	0.94546 (5)	0.0391 (2)
O17	0.8538 (3)	0.41672 (8)	0.80521 (7)	0.0773 (5)
O21	1.16688 (18)	0.98214 (7)	0.93853 (7)	0.0554 (3)
O23	0.6895 (2)	1.09194 (8)	0.84905 (6)	0.0587 (3)
O24	0.8294 (2)	1.19946 (7)	0.87641 (6)	0.0503 (3)
N20	0.82854 (19)	1.02289 (7)	0.94985 (7)	0.0407 (3)
C1	0.6224 (2)	0.77298 (8)	0.95171 (7)	0.0384 (3)
H1A	0.5445	0.7359	0.9751	0.046*
H1B	0.7735	0.7645	0.9584	0.046*
C2	0.5659 (3)	0.84999 (9)	0.97449 (7)	0.0395 (3)
H2A	0.4121	0.8561	0.9735	0.047*
H2B	0.6120	0.8548	1.0161	0.047*
C3	0.6666 (2)	0.91022 (8)	0.93794 (7)	0.0358 (3)
C4	0.6195 (2)	0.89995 (9)	0.87252 (7)	0.0374 (3)
H4A	0.6956	0.9378	0.8495	0.045*
H4B	0.4679	0.9071	0.8657	0.045*
C5	0.6832 (2)	0.82361 (8)	0.85086 (7)	0.0362 (3)
H5	0.8360	0.8189	0.8596	0.043*
C6	0.6611 (3)	0.81504 (9)	0.78390 (7)	0.0436 (4)
H6A	0.5115	0.8170	0.7728	0.052*
H6B	0.7341	0.8561	0.7637	0.052*
C7	0.7545 (3)	0.74192 (9)	0.76422 (7)	0.0431 (4)
H7A	0.9075	0.7430	0.7710	0.052*
H7B	0.7306	0.7357	0.7212	0.052*
C8	0.6612 (2)	0.67605 (9)	0.79700 (7)	0.0386 (3)
H8	0.5108	0.6712	0.7856	0.046*
C9	0.6744 (2)	0.68692 (9)	0.86494 (7)	0.0371 (3)
H9	0.8268	0.6913	0.8742	0.044*
C10	0.5744 (2)	0.76076 (9)	0.88555 (7)	0.0353 (3)
C11	0.5978 (3)	0.61848 (9)	0.89893 (8)	0.0452 (4)
H11A	0.6233	0.6259	0.9417	0.054*
H11B	0.4450	0.6132	0.8931	0.054*
C12	0.7063 (3)	0.54724 (9)	0.87903 (8)	0.0494 (4)
H12A	0.8565	0.5494	0.8895	0.059*
H12B	0.6436	0.5047	0.8999	0.059*
C13	0.6833 (3)	0.53688 (9)	0.81254 (8)	0.0443 (4)
C14	0.7736 (2)	0.60495 (9)	0.78105 (7)	0.0398 (3)
H14	0.9196	0.6106	0.7962	0.048*
C15	0.7951 (3)	0.58031 (10)	0.71633 (8)	0.0469 (4)
H15A	0.6584	0.5812	0.6958	0.056*
H15B	0.8952	0.6119	0.6946	0.056*
C16	0.8780 (3)	0.50133 (10)	0.72248 (8)	0.0510 (4)
H16A	0.8171	0.4691	0.6916	0.061*
H16B	1.0322	0.5004	0.7188	0.061*
C17	0.8113 (3)	0.47586 (10)	0.78369 (9)	0.0529 (4)
C18	0.4553 (3)	0.51990 (11)	0.79537 (9)	0.0525 (4)
H18A	0.4082	0.4756	0.8163	0.079*
H18B	0.4465	0.5117	0.7526	0.079*
H18C	0.3660	0.5616	0.8063	0.079*
C19	0.3361 (2)	0.76058 (10)	0.87603 (8)	0.0434 (4)
H19A	0.2723	0.7225	0.9009	0.065*
H19B	0.3054	0.7503	0.8344	0.065*
H19C	0.2789	0.8089	0.8867	0.065*
C20	0.6240 (2)	0.98918 (9)	0.95876 (8)	0.0393 (3)
H20A	0.5152	1.0133	0.9344	0.047*
H20B	0.5816	0.9906	1.0009	0.047*
C21	0.9800 (2)	0.97169 (9)	0.94408 (8)	0.0416 (4)
C22	0.8665 (2)	1.10123 (9)	0.94325 (8)	0.0422 (3)
H22	1.0215	1.1087	0.9430	0.051*
C23	0.7827 (3)	1.12879 (9)	0.88457 (8)	0.0428 (4)
C24	0.7549 (3)	1.23225 (11)	0.82245 (8)	0.0569 (5)
H24A	0.8032	1.2030	0.7886	0.085*
H24B	0.8091	1.2826	0.8191	0.085*
H24C	0.6017	1.2334	0.8228	0.085*
C25	0.7780 (3)	1.14530 (10)	0.99506 (8)	0.0488 (4)
H25A	0.6250	1.1374	0.9967	0.059*
H25B	0.8021	1.1984	0.9875	0.059*
C26	0.8715 (3)	1.12570 (10)	1.05524 (9)	0.0543 (4)
H26	0.8480	1.0719	1.0623	0.065*
C27	0.7581 (5)	1.16812 (15)	1.10331 (11)	0.0830 (8)
H27A	0.8176	1.1554	1.1419	0.125*
H27B	0.6093	1.1552	1.1027	0.125*
H27C	0.7741	1.2211	1.0964	0.125*
C28	1.1076 (4)	1.13994 (12)	1.05650 (11)	0.0695 (6)
H28A	1.1353	1.1912	1.0452	0.104*
H28B	1.1774	1.1067	1.0286	0.104*
H28C	1.1612	1.1310	1.0965	0.104*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
O3	0.0219 (5)	0.0418 (6)	0.0535 (6)	0.0018 (4)	−0.0026 (4)	−0.0037 (5)
O17	0.1024 (13)	0.0486 (8)	0.0809 (10)	0.0158 (8)	0.0149 (10)	0.0053 (7)
O21	0.0230 (5)	0.0551 (7)	0.0881 (9)	−0.0030 (5)	−0.0003 (6)	−0.0076 (7)
O23	0.0612 (8)	0.0610 (8)	0.0539 (7)	−0.0118 (7)	−0.0124 (6)	−0.0026 (6)
O24	0.0504 (7)	0.0462 (6)	0.0543 (7)	−0.0016 (5)	−0.0060 (6)	0.0030 (5)
N20	0.0248 (6)	0.0399 (7)	0.0573 (8)	−0.0012 (5)	0.0004 (6)	−0.0066 (6)
C1	0.0325 (7)	0.0433 (8)	0.0393 (8)	−0.0026 (6)	0.0019 (6)	0.0035 (6)
C2	0.0309 (7)	0.0476 (9)	0.0401 (8)	−0.0017 (7)	0.0034 (6)	0.0003 (7)
C3	0.0210 (6)	0.0410 (8)	0.0452 (8)	−0.0005 (6)	0.0004 (6)	−0.0014 (6)
C4	0.0294 (7)	0.0388 (8)	0.0440 (8)	−0.0018 (6)	−0.0033 (6)	0.0030 (6)
C5	0.0290 (7)	0.0403 (8)	0.0393 (7)	−0.0028 (6)	−0.0004 (6)	0.0034 (6)
C6	0.0490 (9)	0.0422 (8)	0.0395 (8)	−0.0020 (7)	0.0000 (7)	0.0047 (6)
C7	0.0441 (9)	0.0459 (9)	0.0393 (8)	−0.0032 (7)	0.0022 (7)	0.0030 (7)
C8	0.0333 (7)	0.0414 (8)	0.0410 (8)	−0.0030 (6)	−0.0009 (6)	0.0005 (6)
C9	0.0306 (7)	0.0401 (8)	0.0406 (8)	−0.0014 (6)	−0.0019 (6)	0.0027 (6)
C10	0.0257 (7)	0.0400 (8)	0.0403 (7)	−0.0023 (6)	−0.0015 (6)	0.0024 (6)
C11	0.0479 (9)	0.0430 (8)	0.0447 (8)	−0.0041 (7)	0.0016 (7)	0.0036 (7)
C12	0.0573 (11)	0.0406 (9)	0.0503 (9)	−0.0003 (8)	−0.0017 (8)	0.0057 (7)
C13	0.0427 (9)	0.0399 (8)	0.0503 (9)	−0.0026 (7)	0.0006 (7)	−0.0005 (7)
C14	0.0312 (7)	0.0430 (8)	0.0453 (8)	−0.0029 (6)	−0.0012 (6)	−0.0011 (7)
C15	0.0442 (9)	0.0496 (9)	0.0468 (9)	−0.0017 (8)	0.0036 (7)	−0.0037 (7)
C16	0.0473 (10)	0.0504 (10)	0.0554 (10)	0.0020 (8)	0.0021 (8)	−0.0095 (8)
C17	0.0520 (10)	0.0426 (9)	0.0640 (11)	−0.0032 (8)	0.0004 (9)	−0.0035 (8)
C18	0.0457 (10)	0.0514 (10)	0.0603 (10)	−0.0123 (8)	0.0032 (8)	−0.0049 (8)
C19	0.0276 (7)	0.0485 (9)	0.0540 (9)	−0.0036 (7)	−0.0015 (6)	0.0008 (7)
C20	0.0228 (7)	0.0429 (8)	0.0520 (9)	0.0011 (6)	0.0035 (6)	−0.0040 (7)
C21	0.0259 (7)	0.0468 (9)	0.0520 (9)	0.0002 (6)	−0.0022 (7)	−0.0074 (7)
C22	0.0306 (7)	0.0435 (8)	0.0525 (9)	−0.0025 (6)	−0.0035 (7)	−0.0026 (7)
C23	0.0315 (8)	0.0475 (9)	0.0495 (9)	−0.0006 (7)	0.0007 (7)	−0.0040 (7)
C24	0.0576 (11)	0.0597 (11)	0.0535 (10)	0.0057 (9)	−0.0030 (9)	0.0061 (8)
C25	0.0461 (9)	0.0437 (9)	0.0565 (10)	0.0039 (8)	−0.0033 (8)	−0.0050 (8)
C26	0.0638 (11)	0.0467 (9)	0.0524 (10)	−0.0017 (8)	−0.0087 (9)	0.0007 (8)
C27	0.111 (2)	0.0780 (16)	0.0599 (13)	0.0130 (15)	−0.0044 (14)	−0.0092 (11)
C28	0.0747 (15)	0.0624 (12)	0.0713 (13)	−0.0173 (11)	−0.0277 (12)	0.0102 (10)

Geometric parameters (Å, º)

O3—C21	1.347 (2)	C12—C13	1.522 (2)
O3—C3	1.4826 (16)	C12—H12a	0.9900
O17—C17	1.209 (2)	C12—H12b	0.9900
O21—C21	1.216 (2)	C13—C17	1.523 (2)
O23—C23	1.203 (2)	C13—C14	1.538 (2)
O24—C23	1.330 (2)	C13—C18	1.540 (3)
O24—C24	1.438 (2)	C14—C15	1.536 (2)
N20—C21	1.349 (2)	C14—H14	1.0000
N20—C22	1.450 (2)	C15—C16	1.534 (3)
N20—C20	1.4579 (19)	C15—H15a	0.9900
C1—C2	1.532 (2)	C15—H15b	0.9900
C1—C10	1.543 (2)	C16—C17	1.520 (3)
C1—H1a	0.9900	C16—H16a	0.9900
C1—H1b	0.9900	C16—H16b	0.9900
C2—C3	1.514 (2)	C18—H18a	0.9800
C2—H2a	0.9900	C18—H18b	0.9800
C2—H2b	0.9900	C18—H18c	0.9800
C3—C4	1.520 (2)	C19—H19a	0.9800
C3—C20	1.532 (2)	C19—H19b	0.9800
C4—C5	1.525 (2)	C19—H19c	0.9800
C4—H4a	0.9900	C20—H20a	0.9900
C4—H4b	0.9900	C20—H20b	0.9900
C5—C6	1.528 (2)	C22—C23	1.515 (2)
C5—C10	1.549 (2)	C22—C25	1.527 (2)
C5—H5	1.0000	C22—H22	1.0000
C6—C7	1.521 (2)	C24—H24a	0.9800
C6—H6a	0.9900	C24—H24b	0.9800
C6—H6b	0.9900	C24—H24c	0.9800
C7—C8	1.528 (2)	C25—C26	1.528 (3)
C7—H7a	0.9900	C25—H25a	0.9900
C7—H7b	0.9900	C25—H25b	0.9900
C8—C14	1.520 (2)	C26—C27	1.516 (3)
C8—C9	1.551 (2)	C26—C28	1.532 (3)
C8—H8	1.0000	C26—H26	1.0000
C9—C11	1.540 (2)	C27—H27a	0.9800
C9—C10	1.556 (2)	C27—H27b	0.9800
C9—H9	1.0000	C27—H27c	0.9800
C10—C19	1.539 (2)	C28—H28a	0.9800
C11—C12	1.534 (2)	C28—H28b	0.9800
C11—H11a	0.9900	C28—H28c	0.9800
C11—H11b	0.9900
C21—O3—C3	108.52 (11)	C14—C13—C18	113.55 (15)
C23—O24—C24	116.25 (15)	C8—C14—C15	121.02 (14)
C21—N20—C22	123.03 (13)	C8—C14—C13	113.21 (13)
C21—N20—C20	111.65 (13)	C15—C14—C13	103.93 (13)
C22—N20—C20	125.16 (13)	C8—C14—H14	105.9
C2—C1—C10	114.20 (13)	C15—C14—H14	105.9
C2—C1—H1A	108.7	C13—C14—H14	105.9
C10—C1—H1A	108.7	C16—C15—C14	102.50 (14)
C2—C1—H1B	108.7	C16—C15—H15A	111.3
C10—C1—H1B	108.7	C14—C15—H15A	111.3
H1A—C1—H1B	107.6	C16—C15—H15B	111.3
C3—C2—C1	112.00 (13)	C14—C15—H15B	111.3
C3—C2—H2A	109.2	H15A—C15—H15B	109.2
C1—C2—H2A	109.2	C17—C16—C15	105.65 (14)
C3—C2—H2B	109.2	C17—C16—H16A	110.6
C1—C2—H2B	109.2	C15—C16—H16A	110.6
H2A—C2—H2B	107.9	C17—C16—H16B	110.6
O3—C3—C2	107.47 (12)	C15—C16—H16B	110.6
O3—C3—C4	107.31 (12)	H16A—C16—H16B	108.7
C2—C3—C4	110.99 (13)	O17—C17—C16	124.96 (18)
O3—C3—C20	102.49 (11)	O17—C17—C13	126.41 (18)
C2—C3—C20	115.57 (13)	C16—C17—C13	108.63 (15)
C4—C3—C20	112.22 (13)	C13—C18—H18A	109.5
C3—C4—C5	111.77 (12)	C13—C18—H18B	109.5
C3—C4—H4A	109.3	H18A—C18—H18B	109.5
C5—C4—H4A	109.3	C13—C18—H18C	109.5
C3—C4—H4B	109.3	H18A—C18—H18C	109.5
C5—C4—H4B	109.3	H18B—C18—H18C	109.5
H4A—C4—H4B	107.9	C10—C19—H19A	109.5
C4—C5—C6	112.70 (12)	C10—C19—H19B	109.5
C4—C5—C10	112.72 (13)	H19A—C19—H19B	109.5
C6—C5—C10	112.64 (13)	C10—C19—H19C	109.5
C4—C5—H5	106.0	H19A—C19—H19C	109.5
C6—C5—H5	106.0	H19B—C19—H19C	109.5
C10—C5—H5	106.0	N20—C20—C3	100.96 (12)
C7—C6—C5	110.01 (13)	N20—C20—H20A	111.6
C7—C6—H6A	109.7	C3—C20—H20A	111.6
C5—C6—H6A	109.7	N20—C20—H20B	111.6
C7—C6—H6B	109.7	C3—C20—H20B	111.6
C5—C6—H6B	109.7	H20A—C20—H20B	109.4
H6A—C6—H6B	108.2	O21—C21—O3	122.46 (15)
C6—C7—C8	112.79 (14)	O21—C21—N20	127.47 (16)
C6—C7—H7A	109.0	O3—C21—N20	110.08 (13)
C8—C7—H7A	109.0	N20—C22—C23	110.76 (13)
C6—C7—H7B	109.0	N20—C22—C25	111.86 (14)
C8—C7—H7B	109.0	C23—C22—C25	111.56 (14)
H7A—C7—H7B	107.8	N20—C22—H22	107.5
C14—C8—C7	111.37 (13)	C23—C22—H22	107.5
C14—C8—C9	108.50 (13)	C25—C22—H22	107.5
C7—C8—C9	111.09 (13)	O23—C23—O24	123.69 (16)
C14—C8—H8	108.6	O23—C23—C22	125.17 (16)
C7—C8—H8	108.6	O24—C23—C22	111.12 (14)
C9—C8—H8	108.6	O24—C24—H24A	109.5
C11—C9—C8	111.98 (13)	O24—C24—H24B	109.5
C11—C9—C10	114.46 (13)	H24A—C24—H24B	109.5
C8—C9—C10	112.56 (12)	O24—C24—H24C	109.5
C11—C9—H9	105.7	H24A—C24—H24C	109.5
C8—C9—H9	105.7	H24B—C24—H24C	109.5
C10—C9—H9	105.7	C22—C25—C26	114.59 (15)
C19—C10—C1	109.45 (13)	C22—C25—H25A	108.6
C19—C10—C5	112.06 (13)	C26—C25—H25A	108.6
C1—C10—C5	107.18 (12)	C22—C25—H25B	108.6
C19—C10—C9	111.30 (13)	C26—C25—H25B	108.6
C1—C10—C9	109.40 (12)	H25A—C25—H25B	107.6
C5—C10—C9	107.32 (12)	C27—C26—C25	109.43 (18)
C12—C11—C9	112.89 (14)	C27—C26—C28	111.9 (2)
C12—C11—H11A	109.0	C25—C26—C28	111.28 (18)
C9—C11—H11A	109.0	C27—C26—H26	108.0
C12—C11—H11B	109.0	C25—C26—H26	108.0
C9—C11—H11B	109.0	C28—C26—H26	108.0
H11A—C11—H11B	107.8	C26—C27—H27A	109.5
C13—C12—C11	110.49 (15)	C26—C27—H27B	109.5
C13—C12—H12A	109.6	H27A—C27—H27B	109.5
C11—C12—H12A	109.6	C26—C27—H27C	109.5
C13—C12—H12B	109.6	H27A—C27—H27C	109.5
C11—C12—H12B	109.6	H27B—C27—H27C	109.5
H12A—C12—H12B	108.1	C26—C28—H28A	109.5
C12—C13—C17	117.43 (16)	C26—C28—H28B	109.5
C12—C13—C14	108.76 (14)	H28A—C28—H28B	109.5
C17—C13—C14	100.59 (14)	C26—C28—H28C	109.5
C12—C13—C18	111.41 (15)	H28A—C28—H28C	109.5
C17—C13—C18	104.79 (14)	H28B—C28—H28C	109.5
C10—C1—C2—C3	−54.23 (18)	C7—C8—C14—C13	−179.36 (13)
C21—O3—C3—C2	−145.87 (13)	C9—C8—C14—C13	58.08 (17)
C21—O3—C3—C4	94.70 (14)	C12—C13—C14—C8	−61.12 (18)
C21—O3—C3—C20	−23.64 (17)	C17—C13—C14—C8	174.92 (14)
C1—C2—C3—O3	−64.49 (16)	C18—C13—C14—C8	63.54 (18)
C1—C2—C3—C4	52.57 (17)	C12—C13—C14—C15	165.72 (14)
C1—C2—C3—C20	−178.19 (13)	C17—C13—C14—C15	41.77 (16)
O3—C3—C4—C5	62.36 (15)	C18—C13—C14—C15	−69.62 (17)
C2—C3—C4—C5	−54.80 (16)	C8—C14—C15—C16	−169.60 (14)
C20—C3—C4—C5	174.20 (12)	C13—C14—C15—C16	−41.07 (16)
C3—C4—C5—C6	−173.32 (13)	C14—C15—C16—C17	23.51 (18)
C3—C4—C5—C10	57.81 (16)	C15—C16—C17—O17	−177.7 (2)
C4—C5—C6—C7	172.30 (13)	C15—C16—C17—C13	2.4 (2)
C10—C5—C6—C7	−58.79 (18)	C12—C13—C17—O17	35.3 (3)
C5—C6—C7—C8	54.96 (19)	C14—C13—C17—O17	153.1 (2)
C6—C7—C8—C14	−173.99 (14)	C18—C13—C17—O17	−88.9 (2)
C6—C7—C8—C9	−52.93 (19)	C12—C13—C17—C16	−144.80 (17)
C14—C8—C9—C11	−52.60 (17)	C14—C13—C17—C16	−27.05 (18)
C7—C8—C9—C11	−175.34 (14)	C18—C13—C17—C16	90.97 (17)
C14—C8—C9—C10	176.77 (12)	C21—N20—C20—C3	−17.20 (17)
C7—C8—C9—C10	54.03 (17)	C22—N20—C20—C3	158.28 (15)
C2—C1—C10—C19	−68.09 (17)	O3—C3—C20—N20	23.38 (15)
C2—C1—C10—C5	53.66 (17)	C2—C3—C20—N20	139.93 (13)
C2—C1—C10—C9	169.71 (12)	C4—C3—C20—N20	−91.43 (15)
C4—C5—C10—C19	64.89 (17)	C3—O3—C21—O21	−166.44 (17)
C6—C5—C10—C19	−64.01 (18)	C3—O3—C21—N20	13.80 (18)
C4—C5—C10—C1	−55.21 (16)	C22—N20—C21—O21	7.6 (3)
C6—C5—C10—C1	175.90 (13)	C20—N20—C21—O21	−176.85 (19)
C4—C5—C10—C9	−172.63 (12)	C22—N20—C21—O3	−172.70 (14)
C6—C5—C10—C9	58.47 (16)	C20—N20—C21—O3	2.90 (19)
C11—C9—C10—C19	−62.06 (17)	C21—N20—C22—C23	105.04 (17)
C8—C9—C10—C19	67.30 (16)	C20—N20—C22—C23	−70.0 (2)
C11—C9—C10—C1	59.02 (17)	C21—N20—C22—C25	−129.83 (17)
C8—C9—C10—C1	−171.62 (12)	C20—N20—C22—C25	55.2 (2)
C11—C9—C10—C5	174.99 (13)	C24—O24—C23—O23	2.3 (3)
C8—C9—C10—C5	−55.65 (15)	C24—O24—C23—C22	−179.04 (14)
C8—C9—C11—C12	52.63 (19)	N20—C22—C23—O23	2.9 (2)
C10—C9—C11—C12	−177.72 (13)	C25—C22—C23—O23	−122.44 (19)
C9—C11—C12—C13	−54.7 (2)	N20—C22—C23—O24	−175.77 (13)
C11—C12—C13—C17	170.24 (15)	C25—C22—C23—O24	58.92 (18)
C11—C12—C13—C14	56.97 (19)	N20—C22—C25—C26	61.0 (2)
C11—C12—C13—C18	−68.93 (19)	C23—C22—C25—C26	−174.31 (15)
C7—C8—C14—C15	−55.1 (2)	C22—C25—C26—C27	−175.07 (19)
C9—C8—C14—C15	−177.63 (13)	C22—C25—C26—C28	60.8 (2)