A steroidal phenyldi­hydro-1,3-oxazine derivative

Hewitt, M.; Schneider, T.R.; Szemerédi, Z.; Hajnal, A.; Wölfling, J.; Schneider, G.

doi:10.1107/S0108270100009628

A steroidal phenyldihydro-1,3-oxazine derivative

M. Hewitt, T. R. Schneider, Z. Szemerédi, A. Hajnal, J. Wölfling and G. Schneider

The structure of methyl (6R)-6-(3' [beta]

-acetoxy-5'-androsten-17' [beta]

-yl)-2-phenyl-5,6-dihydro-4H-[1,3]oxazine, C₃₁H₄₁NO₃, synthesized from an azidopregnene derivative, is reported. The dihydro-1,3-oxazine ring is connected in the [beta]

position to the sterane skeleton at C-17'. An R configuration was found at C-6.

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Supporting information

	Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270100009628/qa0336sup1.cif Contains datablocks global, I
	Structure factor file (SHELXL table format) https://doi.org/10.1107/S0108270100009628/qa0336Isup2.sft Supplementary material

CCDC reference: 150402

Comment top

Over the last few decades, increasing attention has been paid to the synthesis of cardenolide and bufadienolide analogues which are expected to have better therapeutic indices (Megges et al., 1978) than the natural glycosteroids. Extensive investigations have shown that for cardiotonic activity, the presence of the 17β side chain containing c═N double-bond moieties is more important than the presence of the unsaturated lactone ring (Thomas et al., 1974; Shiao, 1982; Wicha & Masnyk, 1985a,b). Paryzek & Blaszczyk (1999) recently published a novel approach to the synthesis of the butenolide ring of cardenolides.

3β-Acetoxy-5-pregnen-20-one with methyl formate in the presence of sodium methylate gave 3β-hydroxy-21-hydroxymethylene-5-pregnen-20-one. The reduction of this product with sodium borohydride yielded a trihydroxy compound. This was acetylated, and after selective deacetylation on alumina, we obtained the 21-hydroxymethyl derivative. The selective functionalization of the side chain produced the 21-azidomethyl-20-hydroxy compound. This steroid was treated under Schmidt reaction conditions (Bach & Wolber, 1982) with benzaldehyde in the presence of boron trifluoride diethyl etherate yielding the title compound, (I). The reaction sequence will be published elsewhere (Wölfling et al., 2000).

The crystal structure of (I) shows that the C atom attached to C-17' (C-6) has an R configuration, i.e. the reduction of the C-20 carbonyl of the basic steroid – according to earlier observations (Hirsch & Fujimoto, 1970; Fieser & Fieser, 1959) – ran stereoselectively. The B/C and the C/D ring fusions are trans. Rings A and C adopt chair conformations, while ring B shows a distorted half-chair conformation. Ring D and the 1,3-oxazine ring display slightly distorted half-chair conformations. The sterane skeleton is an equatorial substituent of the 1,3-oxazine ring. The phenyl ring lies nearly in the plane, determined by atoms O20, C70 and N. The total puckering amplitudes (Cremer & Pople, 1975) of the A, B, C, D, 1,3-oxazine and phenyl rings are Q = 0.552, 0.467, 0.573, 0.469, 0.462 and 0.002 Å, respectively.

Crystal structures of some other androstene derivatives have been reported: androst-8-ene (Drouin et al., 1991), androst-9(10)-ene (Ginderow et al., 1993) and androst-4-ene (Anthony et al., 1999). Compounds with the androst-5-ene skeleton were studied, among others, by Cox et al. (1990), Stankovic et al. (1994) and Lazar et al. (1998).

Experimental top

The starting material of our reaction sequence (5-pregnen-3β-ol-20-one) was obtained from the Sigma Chemical Co. (St. Louis, MO).

Computing details top

Data collection: SMART (Bruker 1998); cell refinement: SAINT (Bruker 1998); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); software used to prepare material for publication: SHELXTL.

(6R)-6-(3'β-acetoxy-5'-androsten-17'β-yl)-2-phenyl- 5,6-dihydro-4H-[1,3]oxazine top

Crystal data top

C₃₁H₄₁NO₃	D_x = 1.202 Mg m⁻³
M_r = 475.65	Melting point = 183–186 K
Monoclinic, P2₁	Mo Kα radiation, λ = 0.71073 Å
a = 9.438 (2) Å	Cell parameters from 8192 reflections
b = 8.529 (2) Å	θ = 2.4–25.0°
c = 16.503 (3) Å	µ = 0.08 mm⁻¹
β = 98.38 (3)°	T = 133 K
V = 1314.3 (5) Å³	Block, colourless
Z = 2	0.48 × 0.48 × 0.25 mm
F(000) = 516

Data collection top

STOE-Siemens-Huber four circle diffractometer	2416 independent reflections
Radiation source: fine-focus sealed tube	2177 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.049
Detector resolution: 8.192 pixels mm^-1 pixels mm^-1	θ_max = 25.0°, θ_min = 2.4°
ϕ and ω scans	h = −11→10
Absorption correction: semi-empirical (using intensity measurements) (SADABS; Sheldrick, 1999)	k = 0→10
T_min = 0.964, T_max = 0.981	l = 0→19
14574 measured reflections

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.035	H-atom parameters constrained
wR(F²) = 0.083	w = 1/[σ²(F_o²) + (0.0458P)² + 0.2578P] where P = (F_o² + 2F_c²)/3
S = 1.08	(Δ/σ)_max < 0.001
2416 reflections	Δρ_max = 0.17 e Å⁻³
316 parameters	Δρ_min = −0.14 e Å⁻³
1 restraint	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.015 (2)

Crystal data top

C₃₁H₄₁NO₃	V = 1314.3 (5) Å³
M_r = 475.65	Z = 2
Monoclinic, P2₁	Mo Kα radiation
a = 9.438 (2) Å	µ = 0.08 mm⁻¹
b = 8.529 (2) Å	T = 133 K
c = 16.503 (3) Å	0.48 × 0.48 × 0.25 mm
β = 98.38 (3)°

Data collection top

STOE-Siemens-Huber four circle diffractometer	2416 independent reflections
Absorption correction: semi-empirical (using intensity measurements) (SADABS; Sheldrick, 1999)	2177 reflections with I > 2σ(I)
T_min = 0.964, T_max = 0.981	R_int = 0.049
14574 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.035	1 restraint
wR(F²) = 0.083	H-atom parameters constrained
S = 1.08	Δρ_max = 0.17 e Å⁻³
2416 reflections	Δρ_min = −0.14 e Å⁻³
316 parameters

Special details top

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 (Å²) top

	x	y	z	U_iso*/U_eq	Occ. (<1)
C70	0.7192 (3)	0.4472 (3)	0.08344 (15)	0.0286 (6)*
O20	0.59838 (17)	0.4167 (2)	0.11841 (10)	0.0258 (4)
N	0.7778 (2)	0.3579 (3)	0.03618 (13)	0.0339 (6)
C56	0.8996 (3)	0.6564 (4)	0.07191 (16)	0.0359 (7)
H56	0.9455	0.5869	0.0390	0.043*
C51	0.7775 (3)	0.6058 (3)	0.10421 (14)	0.0268 (6)
C20	0.5544 (3)	0.2527 (3)	0.11728 (15)	0.0261 (6)
H20	0.6222	0.1930	0.1583	0.031*
C52	0.7129 (3)	0.7101 (3)	0.15241 (14)	0.0268 (6)
H52	0.6304	0.6785	0.1750	0.032*
C54	0.8882 (3)	0.9072 (4)	0.13517 (15)	0.0334 (6)
H54	0.9256	1.0097	0.1458	0.040*
C55	0.9536 (3)	0.8054 (4)	0.08726 (17)	0.0382 (7)
H55	1.0359	0.8380	0.0648	0.046*
C53	0.7680 (3)	0.8599 (3)	0.16783 (15)	0.0300 (6)
H53	0.7232	0.9301	0.2009	0.036*
C22	0.7098 (3)	0.2108 (4)	0.00949 (16)	0.0359 (7)
H22A	0.7721	0.1240	0.0332	0.043*
H22B	0.7031	0.2041	−0.0508	0.043*
C21	0.5610 (3)	0.1867 (3)	0.03245 (15)	0.0335 (6)
H21A	0.4892	0.2398	−0.0080	0.040*
H21B	0.5382	0.0733	0.0316	0.040*
O3	−0.33413 (17)	0.7318 (2)	0.43649 (10)	0.0278 (4)
C5	−0.0646 (3)	0.4429 (3)	0.37972 (15)	0.0271 (6)
C15	0.2669 (3)	0.0691 (3)	0.22244 (16)	0.0288 (6)
H15A	0.1788	0.0067	0.2066	0.035*
H15B	0.3191	0.0274	0.2743	0.035*
C8	0.1630 (2)	0.2993 (3)	0.30338 (14)	0.0235 (6)
H8	0.2293	0.2784	0.3552	0.028*
C17	0.4048 (3)	0.2420 (3)	0.14046 (14)	0.0257 (6)
H17	0.3367	0.2834	0.0932	0.031*
C3	−0.2273 (2)	0.6689 (3)	0.38872 (15)	0.0255 (6)
H3	−0.2732	0.6505	0.3310	0.031*
C10	0.0616 (3)	0.5470 (3)	0.36497 (15)	0.0235 (5)
C11	0.2711 (3)	0.5674 (3)	0.28079 (17)	0.0309 (6)
H11A	0.2472	0.6794	0.2708	0.037*
H11B	0.3423	0.5606	0.3311	0.037*
O10	−0.4280 (2)	0.8770 (3)	0.32815 (12)	0.0487 (6)
C9	0.1343 (3)	0.4778 (3)	0.29465 (15)	0.0226 (5)
H9	0.0645	0.4916	0.2434	0.027*
C4	−0.1747 (3)	0.5147 (3)	0.42715 (15)	0.0278 (6)
H4A	−0.2564	0.4419	0.4269	0.033*
H4B	−0.1312	0.5322	0.4847	0.033*
C6	−0.0776 (3)	0.2949 (3)	0.35502 (16)	0.0290 (6)
H6	−0.1556	0.2364	0.3699	0.035*
C60	−0.4264 (3)	0.8371 (3)	0.39826 (15)	0.0296 (6)
C14	0.2320 (2)	0.2434 (3)	0.23029 (15)	0.0235 (5)
H14	0.1618	0.2692	0.1807	0.028*
C2	−0.1030 (3)	0.7819 (3)	0.38934 (16)	0.0280 (6)
H2A	−0.0562	0.7994	0.4463	0.034*
H2B	−0.1383	0.8840	0.3661	0.034*
C80	−0.5268 (3)	0.8983 (4)	0.45336 (17)	0.0364 (7)
H81	−0.5371	0.8203	0.4957	0.055*	0.68 (3)
H82	−0.6206	0.9188	0.4211	0.055*	0.68 (3)
H83	−0.4884	0.9957	0.4793	0.055*	0.68 (3)
H84	−0.5604	1.0015	0.4358	0.055*	0.32 (3)
H85	−0.4782	0.9046	0.5089	0.055*	0.32 (3)
H86	−0.6082	0.8291	0.4519	0.055*	0.32 (3)
C19	0.1658 (3)	0.5600 (3)	0.44587 (15)	0.0316 (6)
H19A	0.2109	0.4580	0.4593	0.047*
H19B	0.1129	0.5924	0.4899	0.047*
H19C	0.2398	0.6379	0.4397	0.047*
C7	0.0210 (3)	0.2128 (3)	0.30549 (17)	0.0313 (6)
H7A	−0.0284	0.2002	0.2487	0.038*
H7B	0.0419	0.1067	0.3285	0.038*
C13	0.3722 (2)	0.3282 (3)	0.21826 (14)	0.0239 (6)
C16	0.3628 (3)	0.0681 (3)	0.15367 (16)	0.0314 (6)
H16A	0.3097	0.0241	0.1026	0.038*
H16B	0.4495	0.0038	0.1701	0.038*
C1	0.0050 (3)	0.7128 (3)	0.33843 (15)	0.0269 (6)
H1A	0.0876	0.7850	0.3413	0.032*
H1B	−0.0405	0.7078	0.2805	0.032*
C18	0.4940 (3)	0.3005 (3)	0.28983 (14)	0.0282 (6)
H18A	0.5784	0.3611	0.2807	0.042*
H18B	0.5182	0.1887	0.2931	0.042*
H18C	0.4628	0.3340	0.3412	0.042*
C12	0.3379 (3)	0.5028 (3)	0.20834 (16)	0.0304 (6)
H12A	0.2707	0.5193	0.1571	0.036*
H12B	0.4270	0.5612	0.2037	0.036*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O20	0.0251 (9)	0.0265 (10)	0.0282 (9)	0.0006 (8)	0.0123 (7)	−0.0017 (8)
N	0.0375 (13)	0.0369 (14)	0.0304 (11)	0.0010 (11)	0.0152 (10)	−0.0070 (10)
C56	0.0333 (15)	0.0424 (17)	0.0348 (14)	−0.0017 (14)	0.0138 (12)	−0.0063 (13)
C51	0.0230 (13)	0.0358 (16)	0.0221 (12)	0.0005 (11)	0.0054 (10)	0.0009 (11)
C20	0.0275 (13)	0.0237 (15)	0.0278 (12)	0.0002 (11)	0.0060 (10)	−0.0026 (11)
C52	0.0227 (12)	0.0354 (16)	0.0224 (11)	0.0018 (12)	0.0036 (10)	0.0013 (11)
C54	0.0341 (15)	0.0332 (16)	0.0330 (14)	−0.0055 (13)	0.0049 (11)	0.0027 (13)
C55	0.0357 (16)	0.0426 (18)	0.0392 (15)	−0.0085 (14)	0.0152 (12)	0.0007 (14)
C53	0.0293 (14)	0.0304 (16)	0.0299 (13)	0.0035 (12)	0.0032 (11)	−0.0031 (11)
C22	0.0437 (16)	0.0350 (17)	0.0315 (13)	0.0037 (13)	0.0139 (12)	−0.0058 (12)
C21	0.0389 (15)	0.0324 (17)	0.0306 (13)	−0.0017 (13)	0.0098 (11)	−0.0072 (12)
O3	0.0235 (8)	0.0316 (10)	0.0303 (9)	0.0029 (8)	0.0103 (7)	−0.0009 (8)
C5	0.0216 (13)	0.0258 (16)	0.0353 (14)	0.0002 (11)	0.0085 (11)	0.0069 (12)
C15	0.0241 (14)	0.0274 (15)	0.0357 (14)	−0.0020 (12)	0.0066 (11)	−0.0028 (12)
C8	0.0198 (12)	0.0211 (13)	0.0300 (13)	−0.0002 (11)	0.0053 (10)	0.0009 (11)
C17	0.0240 (12)	0.0276 (14)	0.0253 (12)	0.0021 (12)	0.0024 (10)	−0.0020 (11)
C3	0.0205 (12)	0.0305 (15)	0.0270 (12)	0.0040 (12)	0.0092 (10)	−0.0004 (12)
C10	0.0210 (12)	0.0216 (14)	0.0287 (12)	−0.0003 (11)	0.0064 (10)	0.0009 (11)
C11	0.0298 (14)	0.0196 (14)	0.0474 (16)	−0.0018 (12)	0.0192 (12)	0.0001 (12)
O10	0.0466 (12)	0.0621 (16)	0.0410 (11)	0.0260 (12)	0.0186 (9)	0.0174 (11)
C9	0.0194 (12)	0.0206 (14)	0.0282 (12)	−0.0007 (10)	0.0047 (10)	0.0023 (10)
C4	0.0270 (14)	0.0243 (14)	0.0337 (14)	−0.0031 (11)	0.0103 (11)	0.0036 (11)
C6	0.0253 (13)	0.0272 (15)	0.0366 (14)	−0.0052 (12)	0.0117 (11)	0.0016 (12)
C60	0.0240 (13)	0.0310 (15)	0.0345 (14)	0.0036 (12)	0.0065 (11)	0.0000 (12)
C14	0.0195 (12)	0.0241 (14)	0.0267 (12)	0.0006 (11)	0.0030 (9)	0.0021 (11)
C2	0.0265 (13)	0.0219 (14)	0.0371 (14)	0.0029 (11)	0.0096 (11)	0.0032 (11)
C80	0.0273 (14)	0.0401 (17)	0.0427 (15)	0.0059 (13)	0.0086 (11)	−0.0070 (14)
C19	0.0262 (13)	0.0378 (16)	0.0313 (13)	0.0001 (13)	0.0055 (11)	−0.0002 (12)
C7	0.0279 (13)	0.0230 (15)	0.0458 (15)	−0.0048 (12)	0.0145 (12)	−0.0037 (12)
C13	0.0203 (12)	0.0251 (14)	0.0274 (12)	0.0001 (11)	0.0067 (10)	−0.0006 (11)
C16	0.0300 (14)	0.0284 (15)	0.0363 (14)	−0.0018 (12)	0.0071 (11)	−0.0070 (12)
C1	0.0249 (12)	0.0226 (14)	0.0353 (13)	0.0016 (11)	0.0110 (11)	0.0044 (11)
C18	0.0239 (13)	0.0321 (15)	0.0294 (12)	−0.0031 (11)	0.0061 (10)	−0.0053 (11)
C12	0.0319 (14)	0.0242 (15)	0.0387 (15)	−0.0020 (11)	0.0173 (12)	0.0045 (12)

Geometric parameters (Å, º) top

C70—N	1.273 (3)	C15—C16	1.551 (3)
C70—O20	1.375 (3)	C8—C14	1.528 (3)
C70—C51	1.482 (4)	C8—C7	1.535 (3)
O20—C20	1.459 (3)	C8—C9	1.550 (3)
N—C22	1.448 (4)	C17—C13	1.549 (3)
C56—C55	1.379 (4)	C17—C16	1.559 (4)
C56—C51	1.406 (4)	C3—C4	1.512 (4)
C51—C52	1.391 (3)	C3—C2	1.517 (4)
C20—C17	1.519 (3)	C10—C19	1.542 (3)
C20—C21	1.519 (3)	C10—C9	1.549 (3)
C52—C53	1.389 (4)	C10—C1	1.552 (4)
C54—C55	1.379 (4)	C11—C12	1.533 (3)
C54—C53	1.385 (4)	C11—C9	1.546 (3)
C22—C21	1.521 (4)	O10—C60	1.204 (3)
O3—C60	1.343 (3)	C6—C7	1.499 (4)
O3—C3	1.469 (3)	C60—C80	1.499 (3)
C5—C6	1.327 (4)	C14—C13	1.546 (3)
C5—C4	1.518 (3)	C2—C1	1.530 (3)
C5—C10	1.533 (3)	C13—C12	1.527 (4)
C15—C14	1.532 (4)	C13—C18	1.542 (3)

N—C70—O20	127.2 (2)	C4—C3—C2	110.1 (2)
N—C70—C51	120.5 (2)	C5—C10—C19	108.4 (2)
O20—C70—C51	112.2 (2)	C5—C10—C9	109.7 (2)
C70—O20—C20	115.31 (19)	C19—C10—C9	112.3 (2)
C70—N—C22	119.4 (2)	C5—C10—C1	109.2 (2)
C55—C56—C51	120.9 (3)	C19—C10—C1	109.2 (2)
C52—C51—C56	118.2 (3)	C9—C10—C1	107.91 (19)
C52—C51—C70	122.5 (2)	C12—C11—C9	112.6 (2)
C56—C51—C70	119.3 (2)	C11—C9—C10	113.2 (2)
O20—C20—C17	109.1 (2)	C11—C9—C8	111.1 (2)
O20—C20—C21	108.5 (2)	C10—C9—C8	113.3 (2)
C17—C20—C21	112.0 (2)	C3—C4—C5	110.0 (2)
C53—C52—C51	120.6 (2)	C5—C6—C7	125.1 (2)
C55—C54—C53	120.0 (3)	O10—C60—O3	123.8 (2)
C54—C55—C56	120.1 (3)	O10—C60—C80	124.4 (3)
C54—C53—C52	120.2 (3)	O3—C60—C80	111.8 (2)
N—C22—C21	115.2 (2)	C8—C14—C15	119.4 (2)
C20—C21—C22	110.1 (2)	C8—C14—C13	115.2 (2)
C60—O3—C3	116.18 (18)	C15—C14—C13	104.2 (2)
C6—C5—C4	120.2 (2)	C3—C2—C1	109.1 (2)
C6—C5—C10	122.8 (2)	C6—C7—C8	113.7 (2)
C4—C5—C10	117.0 (2)	C12—C13—C18	110.8 (2)
C14—C15—C16	102.9 (2)	C12—C13—C14	107.4 (2)
C14—C8—C7	110.0 (2)	C18—C13—C14	112.7 (2)
C14—C8—C9	108.8 (2)	C12—C13—C17	116.0 (2)
C7—C8—C9	109.5 (2)	C18—C13—C17	110.3 (2)
C20—C17—C13	119.0 (2)	C14—C13—C17	99.28 (19)
C20—C17—C16	110.9 (2)	C15—C16—C17	106.5 (2)
C13—C17—C16	104.5 (2)	C2—C1—C10	115.2 (2)
O3—C3—C4	107.57 (19)	C13—C12—C11	111.8 (2)
O3—C3—C2	110.8 (2)

Experimental details

Crystal data
Chemical formula	C₃₁H₄₁NO₃
M_r	475.65
Crystal system, space group	Monoclinic, P2₁
Temperature (K)	133
a, b, c (Å)	9.438 (2), 8.529 (2), 16.503 (3)
β (°)	98.38 (3)
V (Å³)	1314.3 (5)
Z	2
Radiation type	Mo Kα
µ (mm⁻¹)	0.08
Crystal size (mm)	0.48 × 0.48 × 0.25

Data collection
Diffractometer	STOE-Siemens-Huber four circle diffractometer
Absorption correction	Semi-empirical (using intensity measurements) (SADABS; Sheldrick, 1999)
T_min, T_max	0.964, 0.981
No. of measured, independent and observed [I > 2σ(I)] reflections	14574, 2416, 2177
R_int	0.049
(sin θ/λ)_max (Å⁻¹)	0.595

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.035, 0.083, 1.08
No. of reflections	2416
No. of parameters	316
No. of restraints	1
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.17, −0.14

Computer programs: SMART (Bruker 1998), SAINT (Bruker 1998), SAINT, SHELXS97 (Sheldrick, 1997), SHELXL97 (Sheldrick, 1997), SHELXTL.

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Format		BIBTeX
		EndNote
		RefMan
		Refer
		Medline
		CIF
		SGML
		Text
		Plain Text

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A steroidal phenyldi­hydro-1,3-oxazine derivative

Supporting information

A steroidal phenyldihydro-1,3-oxazine derivative