Synthesis of novel steroid-tetrahydroquinoline hybrid molecules and D-homosteroids by intramolecular cyclization reactions

Article abstract of DOI:10.1016/j.steroids.2004.01.004

Steroidal aryliminium salts were prepared from D-seco-pregnene aldehyde 2b, and their BF₃·OEt₂-catalyzed reactions were studied. The nature of the substituent R¹ in the anilines 3-6 essentially influenced the chemoselectivity. Using unsubstituted 3, 4-methoxy- (4) or 4-bromoaniline (5), different tetrahydroquinoline derivatives 7a-13a via intramolecular hetero Diels-Alder reaction were formed. In the case of 4-nitroaniline (6) the N-arylamino-D-homopregnane (14a) were also obtained. We assume, that an intramolecular Prins reaction led to this type of fluoro-D-homosteroid. The main products represent a new class of tetrahydroquinolino-androstenes.

Full text of DOI:10.1016/j.steroids.2004.01.004

Steroids 69 (2004) 301–312
Synthesis of novel steroid-tetrahydroquinoline hybrid molecules and
d-homosteroids by intramolecular cyclization reactions
Angéla Magyara, János Wölflinga, Melanie Kubasb, Jose Antonio Cuesta Seijob,
Madhumati Sevvanab, Regine Herbst-Irmerb, Péter Forgóa, Gyula Schneidera,∗
a
Department of Organic Chemistry, University of Szeged, H-6720 Szeged, Dóm tér 8., Hungary
b
Department of Structural Chemistry, University of Göttingen, Tammannstr. 4, D-37077 Göttingen, Germany
Received 11 September 2003; received in revised form 20 January 2004; accepted 26 January 2004
Abstract
Steroidal aryliminium salts were prepared from d-seco-pregnene aldehyde 2b, and their BF3·OEt2-catalyzed reactions were studied.
The nature of the substituent R1 in the anilines 3–6 essentially influenced the chemoselectivity. Using unsubstituted 3, 4-methoxy- (4) or
4-bromoaniline (5), different tetrahydroquinoline derivatives 7a–13a via intramolecular hetero Diels-Alder reaction were formed. In the
case of 4-nitroaniline (6) the N-arylamino-d-homopregnane (14a) were also obtained. We assume, that an intramolecular Prins reaction
led to this type of fluoro-d-homosteroid. The main products represent a new class of tetrahydroquinolino-androstenes.
© 2004 Elsevier Inc. All rights reserved.
Keywords: Cycloaddition; Hetero Diels-Alder reaction; d-Homosteroids; Intramolecular Prins reaction; Quinolines
1. Introduction
Our goal was to prepare tetrahydroquinoline steroid hy-
brid molecules via a Lewis acid-catalyzed reaction of an
aldehyde steroid fragment 2, containing a substituted allyl
and a formyl group in suitable positions, and various ani-
lines 3–6. We planned to perform the reaction in consecu-
tive steps: amine-oxo condensation and a subsequent hetero
Diels-Alder reaction. Additionally, we intended to investi-
gate the influence of the relatively rigid steroidal skeleton
and the different substituents of the aniline on the stereose-
lectivity of these reactions.
A significant aim in organic chemistry is the development
of new types of pharmacologically active substances. The
coupling of two or more natural products to make hybrids
leads to an almost inexhaustible reservoir of new types of
compounds with diverse structures. We recently made a new
type of pharmacologically interesting, hybrid natural product
from estrone and the highly biologically active mycotoxin
talaromycin B [1], and in vitro tests demonstrated its strong
cytotoxic activity against human cells [2]. The combination
of a toxin with a steroid was chosen in light of the fact that
steroids are able to penetrate the cell membrane and bind
the cell nucleus [3].
2. Experimental
Melting points (mp) were determined on a Kofler
hot-stage apparatus and are uncorrected. Specific rota-
tions were measured in chloroform (c 1, if not mentioned
otherwise) with a POLAMAT-A (Zeiss-Jena) polarimeter
and are given in units of 10−1 degree cm2 g−1. Elemen-
tal analyses were performed with a Perkin-Elmer CHN
analyzer model 2400. Thin-layer chromatography: silica
gel 60 F254; layer thickness 0.2 mm (Merck); solvent sys-
tems (ss): (A) ethyl acetate/dichloromethane (5:95 v/v);
(B) dichloromethane; (C) tert-butyl methyl ether/light
petroleum (1:1 v/v); (D) ethyl acetate/dichloromethane
As part of a program of research on steroid hybrids,
we were interested in the synthesis of various kinds of
tetrahydroquinolines condensed to the androstane skeleton.
Tetrahydroquinolines occur naturally in the human body [4].
One such compound, oxamniquine has an antiarrhythmic ef-
fect, while dynemicin, which has a complex structure based
on the tetrahydroquinoline system, is a natural antitumor an-
tibiotic [5].
∗
Corresponding author. Tel.: +36-62-544276; fax: +36-62-544200.
E-mail address: schneider@chem.u-szeged.hu (G. Schneider).
0039-128X/$ – see front matter © 2004 Elsevier Inc. All rights reserved.
doi:10.1016/j.steroids.2004.01.004

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A. Magyar et al. / Steroids 69 (2004) 301–312
(30:70 v/v); (E) tert-butyl methyl ether/dichloromethane
(20:80 v/v); (F) ethyl acetate/dichloromethane (10:90
v/v); (G) ethyl acetate/dichloromethane (20:80 v/v); (H)
tert-butyl methyl ether/dichloromethane (10:90 v/v); de-
tection with iodine or UV (365 nm) after spraying with
50% H3PO4 and heating at 100–120 ◦C for 10 min. Flash
chromatography: silica gel 60, 40–63 ␮m. 1H NMR spectra
were recorded at 500 MHz in CDCl3 solution with a Bruker
DRX-500 instrument, using TMS as the internal standard.
13C NMR spectra were recorded with the same instrument
at 125 MHz, using the CDCl3 triplet (δ 77.0) as a reference
(if not stated otherwise). EI-MS spectra were recorded on a
Varian MAT 311A instrument with an ionization energy of
70 eV.
Diffraction data for compound 7d were collected on a
Stoe-Huber-Siemens four-circle diffractometer at −140 ◦C
and were processed by SMART, SAINT, and SADABS
(BrukerAXS, 2002). Intensity data for compound 11c were
collected on a Stoe IPDS II two-circle diffractometer at
−140 ◦C and processed with the program X-Area (Stoe,
2002). In both cases, graphite-monochromated Mo K␣ ra-
diation (λ = 0.71073 Å) was used. Compound 14c was
measured on a Bruker rotating anode equipped with Os-
mic focusing mirrors and a Bruker SMART6000 4K CCD
detector using Cu K␣ radiation (λ = 1.54178 Å), and the
data were processed with Proteum, SAINT, and SADABS
(BrukerAXS, 2002). The structures were solved by direct
methods using SHELXS [13] and refined against Fo2 us-
ing SHELXL (Sheldrick, G.M., SHELXL-97, Program for
Structure Refinement, Universität Göttingen, 1997). All
non-hydrogen atoms were refined anisotropically, hydro-
gen atoms in hydrogen bonds were refined isotropically,
and the riding model was used for the remaining hydrogen
atoms.
stirred until completion of the reaction (monitored by TLC)
and then worked up. Water (50 ml) was added, and the pre-
cipitate was separated, washed with water, and dried. The
crude products (7b–14b, 7d–14d) were purified by flash
chromatography or by recrystallization.
2.1.3. C: Preparation of 3β-acetoxy-N-acetyl compounds
The steroid derivatives (7a–13a, 1.0 mmol) were dis-
solved in acetic anhydride (10 ml) and KOAc (1.0 g,
10.2 mmol) was added. The solution was heated at 80 ◦C,
which yielded a deep-colored mixture. It was worked up
by the addition of water (30 ml) and extracted with CH2Cl2
(3 × 30 ml). The combined organic phases were washed
with water (2 × 30 ml), dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude products (7c–13c) were
purified by recrystallization or by flash chromatography.
2.1.4. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-acetoxy-4ꢀ-methyl-(16β,
17α)-androsta-5,16-dieno[17,16-b]quinoline (7a) and
1ꢀ,4ꢀ,16,17-tetrahydro-3β-acetoxy-4ꢀ-methyl-(16α,17α)-
androsta-5,16-dieno[17,16-b]quinoline (11a)
d-seco-Steroid 2b (359 mg, 1.0 mmol) was reacted with
3 (0.1 ml, 1.1 mmol) by general procedure A. The result-
ing crude product was chromatographed on silica gel with
dichloromethane as the eluent, yielding pure 11a (51 mg,
12%), mp 210–222 ◦C, Rf = 0.4 (ss B), [α]2D0 = −82
(Found C, 80.54; H, 8.95; N, 3.41. C29H39NO2 requires C,
80.33, H 9.07, N 3.23%); 1H NMR: δ = 0.82 (s, 3H, 18-H3),
1.03 (s, 3H, 19-H3), 1.34 (d, J = 6.9 Hz, 3H, 21-H3), 2.03
(s, 3H, CH3CO), 2.10–2.17 (m, 1H), 2.33 (m, 2H, 4-H2),
2.72 (m, 1H, 20-H), 3.63 (m, 1H, 16-H), 3.68 (br s, 1H,
N-H), 4.60 (m, 1H, 3-H), 5.38 (m, 1H, 6-H), 6.49 (dd, J =
7.8, 0.9 Hz, 1H, 6ꢀ-H), 6.70 (td, J = 7.3, 0.9 Hz, 1H, 4ꢀ-H),
6.97 (m, 1H, 5ꢀ-H), 7.09 (d, J = 7.3 Hz, 1H, 3ꢀ-H) ppm.
13C NMR: δ = 14.9, 19.3, 20.6, 21.0, 21.4, 27.7, 29.7, 31.2,
32.0, 35.4, 36.7, 37.0, 38.1, 39.4, 43.0, 50.2, 54.1, 54.5,
58.7, 73.9 (C-3), 113.8, 118.2, 122.3 (C-6), 126.1, 126.2,
130.2, 139.8 (C-5), 146.1, 170.5 (CH3CO) ppm. EI-MS m/z
(relative intensity): 434 (30), 433 (M+, 100), 418 (10), 145
(15), 130 (16), 43 (12). Continued elution resulted in 7a
2.1. General procedures
2.1.1. A: Preparation of the Diels-Alder adducts 7a–13a
and the d-homosteroid 14a
A solution of 2b (359 mg, 1.0 mmol) and the aniline (3–6,
1.1 mmol) in dichloromethane (10 ml) was heated under a
nitrogen atmosphere in the presence of molecular sieve (4 Å,
150 mg) for 1.5 h at 40 ◦C. The sieve was filtered off, and
BF3·OEt2 (a 1 M solution in CH2Cl2, 1 ml, 1 mmol) was
added dropwise at 0 ◦C. The reaction was continued un-
til complete conversion was achieved (TLC). In the next
step, saturated NaHCO3 solution was added, and the mix-
ture was extracted with CH2Cl2 (3 × 15 ml). The combined
organic layers were washed with brine, dried over anhydrous
Na2SO4, and evaporated. The crude products (7a–14a) were
purified by flash chromatography.
(343 mg, 79%), mp 242–245 ◦C, Rf = 0.2 (ss B), [α]20
=
+18. (Found C, 80.41; H, 9.14; N, 3.31. C29H39NO2D re-
quires C, 80.33; H, 9.07; N 3.23%); 1H NMR: δ = 0.84 (s,
3H, 18-H3), 1.05 (s, 3H, 19-H3), 1.01–1.09 (m, 1H), 1.15
(m, 1H), 1.32 (d, J = 6.4 Hz, 3H, 21-H3), 1.30–1.40 (m,
2H), 1.44–1.66 (m, 8H), 1.83–1.91 (m, 2H), 2.03 (s, 3H,
CH3CO), 1.94–2.05 (m, 2H), 2.33 (m, 2H, 4-H2), 3.07 (m,
1H, 20-H), 3.46 (m, 1H, 16-H), 3.92 (br s, 1H, N-H), 4.61
(m, 1H, 3-H), 5.39 (m, 1H, 6-H), 6.58 (d, J = 7.8 Hz, 1H,
6ꢀ-H), 6.74 (t, J = 7.8 Hz, 1H, 4ꢀ-H), 6.98 (t, J = 7.8 Hz,
1H, 5ꢀ-H), 7.22 (d, J = 7.8 Hz, 1H, 3ꢀ-H) ppm. 13C NMR:
δ = 12.7, 19.1, 19.3, 20.5, 21.4, 27.7, 30.5, 31.6, 31.6, 34.3,
36.6, 36.9, 38.1, 39.0, 42.0, 50.3, 55.2, 56.7, 59.6, 73.9 (C-3),
116.4, 118.7, 122.3 (C-6), 126.4, 128.0, 129.9, 139.9 (C-5),
146.5, 170.5 (CH3CO) ppm. EI-MS m/z (relative intensity):
434 (30), 433 (M+, 100).
2.1.2. B: Alkaline hydrolysis
The steroid derivatives (7a–14a, 7c–14c, 0.25 mmol)
were suspended in methanol (25 ml), and NaOCH3 (25 mg,
0.46 mmol) in methanol (5 ml) was added. The mixture was

A. Magyar et al. / Steroids 69 (2004) 301–312
303
2.1.5. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-acetoxy-6ꢀ-methoxy-4ꢀ-
methyl-(16β,17α)-androsta-5,16-dieno[17,16-b]quinoline
(8a) and 1ꢀ,4ꢀ,16,17-tetrahydro-3β-acetoxy-6ꢀ-methoxy-4ꢀ-
methyl-(16α,17α)-androsta-5,16-dieno[17,16-b]quinoline
(12a)
2H, 4-H2), 2.69 (m, 1H, 20-H), 3.63 (m, 1H, 16-H), 3.71 (br
s, 1H, N-H), 4.60 (m, 1H, 3-H), 5.38 (m, 1H, 6-H), 6.35 (d,
J = 8.3 Hz, 1H, 6ꢀ-H), 7.04 (dd, J = 8.3, 1.6 Hz, 1H, 5ꢀ-H),
7.16 (d, J = 1.6 Hz, 1H, 3ꢀ-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.7, 19.3, 20.6, 21.3, 21.4, 27.7, 29.7, 31.1,
31.9, 35.5, 36.7, 36.9, 38.1, 39.2, 43.0, 50.2, 53.6, 54.6,
58.0, 73.8 (C-3), 109.6, 115.1, 122.2 (C-6), 128.8, 129.2,
132.1, 139.9 (C-5), 144.8, 170.5 (CH3CO) ppm. EI-MS m/z
(relative intensity): 514 (30), 513 ([M+2]+, 100), 512 (35),
511 (M+, 98), 210 (16). Continued elution resulted in 9a
d-seco-Steroid 2b (359 mg, 1.0 mmol) was reacted with 4
(135 mg, 1.1 mmol) by general procedure A. Column chro-
matography of the resulting crude product on silica gel with
ethyl acetate/dichloromethane (5:95 v/v) afforded pure 12a
(87 mg, 19%), mp 192–194 ◦C, Rf = 0.5 (ss A), [α]20
=
−105. (Found C, 77.89; H, 9.02; N, 3.35. C30H41NOD3 re-
(395 mg, 77%), mp 240–242 ◦C, Rf = 0.1 (ss B), [α]20
=
quires C, 77.71; H, 8.91; N, 3.02%); H NMR: δ = 0.89
+60. (Found C, 68.05; H, 7.53; N, 2.86. C29H38BrNOD2 re-
quires C, 67.96; H, 7.47; N, 2.73%); 1H NMR: δ = 0.82 (s,
3H, 18-H3), 1.05 (s, 3H, 19-H3), 1.00–1.09 (m, 1H), 1.14
(m, 1H), 1.29 (d, J = 6.4 Hz, 3H, 21-H3), 1.25–1.39 (m,
2H), 1.41–1.67 (m, 8H), 1.81–1.91 (m, 2H), 1.93–2.01 (m,
2H), 2.03 (s, 3H, CH3CO), 2.27–2.38 (m, 2H, 4-H2), 3.01
(m, 1H, 20-H), 3.41 (m, 1H, 16-H), 3.94 (br s, 1H, N-H),
4.60 (m, 1H, 3-H), 5.37 (m, 1H, 6-H), 6.43 (d, J = 8.7 Hz,
1H, 6ꢀ-H), 7.04 (dd, J = 8.7, 1.7 Hz, 1H, 5ꢀ-H), 7.29 (d,
J = 1.7 Hz, 1H, 3ꢀ-H) ppm. 13C NMR: δ = 12.6, 19.0,
19.3, 20.4, 21.4, 27.7, 30.4, 31.5, 31.6, 34.4, 36.6, 36.9,
38.1, 38.9, 42.0, 50.3, 55.3, 56.7, 58.9, 73.8, 110.5, 117.7,
122.2 (C-6), 129.1, 130.7, 132.0, 139.9 (C-5), 145.6, 170.4
(CH3CO) ppm. EI-MS m/z (relative intensity): 514 (28),
513 ([M + 2]+, 100), 512 (32), 511 (M+, 95).***********
1
(s, 3H, 18-H3), 1.04 (s, 3H, 19-H3), 0.96–1.18 (m, 3H),
1.19–1.32 (m, 2H), 1.35 (d, J = 6.8 Hz, 3H, 21-H3),
1.45–1.67 (m, 6H), 2.03 (s, 3.H, OAc-H3), 1.82–2.13 (m,
5H), 2.33 (m, 2H), 2.71 (m, 1H), 3.49 (m, 1H), 3.75 (s,
3H, OMe-H3), 4.61 (m, 1H, 3-H), 5.38 (m, 1H, 6-H), 6.49
(d, J = 8.4 Hz, 1H, 6ꢀ-H), 6.57 (dd, J = 8.4, 2.4 Hz, 1H,
5ꢀ-H), 6.76 (d, J = 2.4 Hz, 1H, 3ꢀ-H) ppm. 13C NMR:
δ = 15.1, 19.2, 19.2, 20.7, 21.3, 27.7, 30.1, 31.1, 32.0,
34.5, 36.6, 36.9, 38.1, 39.8, 43.0, 50.1, 54.2, 55.7, 56.0,
59.2, 73.8, 110.6, 112.4, 114.5, 122.3 (C-6), 133.2, 139.7
(C-5), 140.8, 153.0, 170.4 (OAc-C) ppm. EI-MS m/z (rela-
tive intensity): 463 (M+, 100), 464 (30). Continued elution
resulted in 8a (331 mg, 71%), mp 182–185 ◦C, Rf = 0.2
(ss A), [α]D20 = +28. (Found C, H. C30H41NO3 requires C
1
77.71, H 8.91, N 3.02, O 10.35%); H NMR: δ = 0.83 (s,
2.1.7. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-acetoxy-6ꢀ-nitro-4ꢀ-
methyl-(16β,17α)-androsta-5,16-dieno[17,16-b]quinoline
(10a) and 3β-acetoxy-16β-[N-(4ꢀ-nitro)-phenyl]-amino-
17a␤-fluoro-17␣-methyl-d-homo-androsta-5-ene (14a)
d-seco-Steroid 2b (359 mg, 1.0 mmol) was reacted with
6 (152 mg, 1.1 mmol) by general procedure A. The result-
ing crude product was chromatographed on silica gel with
tert-butyl methyl ether/light petroleum (25:75 v/v), yield-
ing pure 14a (61 mg, 12%), mp 145–155 ◦C, Rf = 0.6
(ss C), [α]2D0 = +16. (Found C, 69.72; H, 8.02; N, 5.78.
3H, 18-H3), 1.05 (s, 3H, 19-H3), 0.99–1.09 (m, 1H), 1.15
(m, 1H), 1.31 (d, J = 8.95 Hz, 3H, 21-H3), 1.27–1.41 (m,
2H), 1.43–1.68 (m, 8H), 1.81–1.92 (m, 2H), 2.03 (s, 3H,
CH3CO), 1.93–2.08 (m, 2H), 2.34 (m, 2H, 4-H2), 3.04 (m,
1H, 20-H), 3.40 (m, 1H, 16-H), 3.74 (s, 3H, OMe-H3), 4.61
(m, 1H, 3-H), 5.38 (m, 1H, 6-H), 6.56 (d, J = 8.48 Hz,
1H, 6ꢀ-H), 6.60 (dd, J = 8.48, 2.06 Hz, 1H, 5ꢀ-H), 6.81 (d,
J = 2.06 Hz, 1H, 3ꢀ-H) ppm. 13C NMR: δ = 12.7, 19.3
(2C), 20.5, 21.4, 27.7, 30.6, 31.6, 31.6, 34.5, 36.6, 36.9,
38.1, 39.0, 42.0, 50.3, 55.2, 55.7, 57.2, 59.7, 73.9 (C-3),
112.1, 113.8, 117.4, 122.3 (C-6), 131.5, 139.8 (C-5), 140.3,
153.0, 170.4 (CH3CO) ppm. EI-MS m/z (relative intensity):
463 (M+, 100), 464 (35).
1
C29H39FN2O4 requires C, 69.85; H, 7.88; N, 5.62%), H
NMR: δ = 0.93 (s, 3H, 18-H3), 1.00 (s, 3H, 19-H3), 1.11
(d, J = 5.2 Hz, 3H, 21-H3), 2.02 (s, 3H, OAc-H3), 3.08 (qd,
J = 10.5, 4.9 Hz, 1-H, 17-H), 3.47 (s, 1H, N-H), 3.73 (dd,
J = 47.9, 10.5 Hz, 1H, 17a-H), 4.47 (m, 1H, 16-H), 4.60
(m, 1H, 3-H), 5.32 (m, 1H, 6-H), 6.50 (d, J = 9.2 Hz, 2H,
2.1.6. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-acetoxy-6ꢀ-bromo-4ꢀ-
methyl-(16β,17α)-androsta-5,16-dieno[17,16-b]quinoline
(9a) and 1ꢀ,4ꢀ,16,17-tetrahydro-3β-acetoxy-6ꢀ-bromo-4ꢀ-
methyl-(16α,17α)-androsta-5,16-dieno[17,16-b]quinoline
(13a)
d-seco-Steroid 2b (359 mg, 1.0 mmol) was reacted with
5 (189 mg, 1.1 mmol) by general procedure A. The result-
ing crude product was chromatographed on silica gel with
dichloromethane, affording pure 13a (82 mg, 16%), mp
214–216 ◦C, Rf = 0.6 (ss B), [α]20 = −112. (Found C,
68.02; H, 7.62; N, 2.36. C29H38BrDNO2 requires C, 67.96;
H, 7.47; N, 2.73%); 1H NMR: δ = 0.77 (s, 3H, 18-H3), 1.03
(s, 3H, 19-H3), 1.31 (d, J = 6.9 Hz, 3H, 21-H3), 0.94–1.36
(m, 5H), 1.42–1.67 (m, 6H), 1.81–1.94 (m, 3H), 2.03 (s,
3H, CH3CO), 1.94–2.07 (m, 1H), 2.15 (m, 1H), 2.33 (m,
(2ꢀ + 6ꢀ)-H), 8.06 (d, J = 9.2 Hz, 2H, (3ꢀ + 5ꢀ)-H) ppm. 13
C
NMR: δ = 11.9, 15.0, 19.2, 19.5, 21.3, 27.7, 30.4, 30.7,
31.8, 36.5, 36.6, 36.8, 37.8, 38.0, 39.1 (d, J = 18.9 Hz,
C-17), 45.8 (d, J = 6.3 Hz), 49.4, 55.9 (d, J = 10.8 Hz),
73.7 (C-3), 103.2 (d, J = 183.7 Hz, C-17a), 111.0 (2C,
C-2ꢀ and –6ꢀ). 121.7 (C-6), 126.6 (2C, C-3ꢀ and -5ꢀ), 137.8
(C-4ꢀ), 139.5 (C-5), 153.0 (C-1ꢀ), 170.5 (OAc) ppm. EI-MS
m/z (relative intensity): 498 (M+, 15), 438 ([M − AcOH]+,
100). Continued elution resulted in 10a (347 mg, 73%), mp
252–254 ◦C, Rf = 0.5 (ss C), [α]2D0 = +232. (Found C,
72.98; H, 8.21; N, 6.02. C29H38N2O4 requires C, 72.77; H,
8.00; N 5.85%); 1H NMR: δ = 0.85 (s, 3H, 18-H3), 1.06 (s,
3H, 19-H3), 1.01–1.10 (m, 1H), 1.15 (m, 1H), 1.38 (d, J =

304
A. Magyar et al. / Steroids 69 (2004) 301–312
6.7 Hz, 3H, 21-H3), 1.29–1.42 (m, 2H), 1.44–1.76 (m, 8H),
1.86 (m, 2H), 2.04 (s, 3H, CH3CO), 1.93–2.08 (m, 2H), 2.33
(m, 2H, 4-H2), 3.06 (m, 1H, 20-H), 3.59 (m, 1H, 16-H), 4.60
(m, 1H, 3-H), 4.84 (s, 1H, N-H), 5.38 (m, 1H, 6-H), 6.45 (d,
J = 8.9 Hz, 1H, 6ꢀ-H), 7.88 (dd, J = 8.9, 2.5 Hz, 1H, 5ꢀ-H),
8.13 (d, J = 2.5 Hz, 1H, 3ꢀ-H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 12.4, 18.2, 19.3, 20.4, 21.4, 27.7, 30.0, 31.5,
31.5, 34.5, 36.6, 36.9, 38.1, 38.7, 41.9, 50.3, 55.5, 56.4, 57.8,
73.8 (C-3), 114.1, 122.0 (C-6), 123.6, 124.7, 128.3, 138.6,
140.0 (C-5), 152.1, 170.6 (CH3CO) ppm. EI-MS m/z (rela-
tive intensity): 478 (M+, 4), 418 ([M − AcOH]+, 8), 129
(16), 91 (100), 55 (18), 43 (22).
2.1.10. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-hydroxy-1ꢀ-acetyl-4ꢀ-
methyl-(16β,17α)-androsta-5,16-dieno[17,16-b]quinoline
(7d)
7c (119 mg, 0.25 mmol) was hydrolyzed by general pro-
cedure B. Recrystallization from dichloromethane/light
petroleum afforded glossy white needles 7d (101 mg,
93%), mp 215–218 ◦C, Rf = 0.4 (ss E), [α]2D0 = −134.
(Found C, 80.46; H, 8.98; N, 3.46. C29H39NO2 requires
1
C, 80.33; H, 9.07; N 3.23%); H NMR: δ = 0.88 (s, 3H,
18-H3), 1.03 (s, 3H, 19-H3), 1.35 (d, J = 6.9 Hz, 3H,
21-H3), 2.18 (s, 3H, CH3CO), 0.96–2.35 (m, 18H), 2.88
(m, 1H, 20-H), 3.52 (m, 1H, 3-H), 3.88 (td, J = 11.0,
5.5 Hz, 1H, 16-H), 5.35 (m, 1H, 6-H), 7.09–7.19 (m,
3H), 7.25 (m, 1H, 6ꢀ-H) ppm. 13C NMR: δ = 12.9, 18.1,
19.4, 20.4, 24.8, 29.8, 31.4, 31.4, 31.5, 35.6, 36.5, 37.1,
38.5, 40.5, 42.3, 50.3, 55.9, 60.7, 64.4, 71.6 (C-3), 121.5
(C-6), 124.8, 125.3, 125.5, 126.2, 139.8, 140.7 (C-5),
140.9, 172.6 (CH3CO) ppm. EI-MS m/z (relative inten-
sity): 434 (28), 433 (M+, 100), 391 ([M + H − Ac]+,
40), 296 (25), 144 (10). Crystal data: C29H39NO2 × 0.5
CH2Cl2, Mr = 476.07, monoclinic, space group C2,
a = 30.218(3) Å, b = 6.050(2) Å, c = 14.218(2) Å,
2.1.8. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-hydroxy-4ꢀ-methyl-(16β,
17α)-androsta-5,16-dieno [17,16b] quinoline (7b)
7a (108 mg, 0.25 mmol) was hydrolyzed by general pro-
cedure B. Recrystallization from methanol afforded 7b
(169 mg, 70%), mp 216–219 ◦C, Rf = 0.4 (ss D), [α]2D0
=
−13. (Found C, 82.67; H, 9.73, N, 3.67. C27H37NO re-
quires C, 82.81; H, 9.52; N, 3.58%); 1H NMR: δ = 0.85 (s,
3H, 18-H3), 1.04 (s, 3H, 19-H3), 0.97–1.15 (m, 2H), 1.33
(d, J = 6.4 Hz, 1H, 21-H3), 1.30–1.41 (m, 2H), 1.44–1.69
(m, 8H), 1.85 (m, 2H), 2.00 (m, 2H), 2.20–2.35 (m, 2H),
3.08 (m, 1H, 20-H), 3.46 (m, 1H, 16-H), 3.53 (m, 1H, 3-H),
5.36 (m, 1H, 6-H), 6.59 (d, J = 7.8 Hz, 1H, 6ꢀ-H), 6.75
(dd, J = 7.8, 7.3 Hz, 1H, 5ꢀ-H), 6.98 (dd, J = 7.8, 7.3 Hz,
1H, 4ꢀ-H), 7.23 (d, J = 7.8 Hz, 1H, 3ꢀ-H) ppm. 13C NMR:
δ = 12.7, 19.2, 19.4, 20.6, 30.5, 31.6, 31.6, 31.6, 34.3, 36.6,
37.2, 39.1, 42.1, 42.3, 50.4, 55.4, 56.8, 59.6, 71.7 (C-3),
116.5, 118.8, 121.4 (C-6), 126.4, 128.0, 130.0, 141.0 (C-5),
146.5 ppm. EI-MS m/z (relative intensity): 392 (30), 391
(M+, 100), 390 (10), 144 (8).
β = 100.12(4)◦, V = 2558.9(10) Å3, Z = 4, ρcalc
=
1.236 g cm−3, F(000) = 1028, µ(Mo K␣) = 0.176 cm−1
,
min/max transmission 0.8867/0.9171, crystal dimensions
0.7 mm × 0.5 mm × 0.5 mm, 2.17◦ < Θ < 27.54◦, 12,706
reflections were collected, of which 5032 were independent
(Rint = 0.0417) and 5032 were used for refinement. For
the final refinement of 324 parameters, two restraints were
used. The R-values were: R1 = Σ|Fo − Fc|/ΣFo = 0.0441
ꢀ
ꢀ
for I > 2σ(I), and wR2 = [ w(Fo2 − Fc2)2/ wFo4]1/2
=
0.1189 for all data; max/min residual electron density:
0.26/−0.25 eÅ−3
.
2.1.9. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-acetoxy-1ꢀ-acetyl-4ꢀ-
methyl-(16β,17α)-androsta-5,16-dieno[17,16-b]quinoline
(7c)
2.1.11. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-hydroxy-6ꢀ-methoxy-4ꢀ-
methyl-(16β,17α)-androsta-5,16-dieno[17,16-b]quinoline
(8b)
7a (434 mg, 1.0 mmol) was acetylated by general pro-
cedure C. Column chromatography on silica gel with
tert-butyl methyl ether/dichloromethane (10:90 v/v) af-
forded 7c (428 mg, 90%) mp 202–206 ◦C, Rf = 0.6 (ss
E), [α]2D0 = −144. (Found C, 78.41; H, 8.76; N, 3.05.
C31H41NO3 requires C, 78.28; H, 8.69; N 2.94%); 1H
NMR: δ = 0.88 (s, 3H, 18-H3), 1.04 (s, 3H, 19-H3),
0.98–1.07 (m, 1H), 1.13 (td, J = 13.8, 3.8 Hz, 1H), 1.35
(d, J = 6.9 Hz, 3H, 21-H3), 1.24–1.43 (m, 2H), 1.44–1.64
(m, 6H), 2.02 (s, 3H, CH3COO), 1.78–2.04 (m, 5H), 2.17
(s, 3H, CH3CON), 2.25–2.36 (m, 3H), 2.87 (m, 1H, 20-H),
3.88 (td, J = 11.0, 5.8 Hz, 1H, 16-H), 4.60 (m, 1H, 3-H),
5.37 (m, 1H, 6-H), 7.08–7.19 (m, 3H, 3ꢀ-, 4ꢀ- and 5ꢀ-H),
7.25 (d, J = 7.3 Hz, 1H, 6ꢀ-H) ppm. 13C NMR: δ = 12.9,
18.0, 19.2, 20.4, 21.3, 24.7, 27.7, 29.7, 31.3, 31.4, 35.6,
36.6, 36.8, 38.0, 38.5, 40.5, 50.2, 55.8, 60.6, 64.4, 73.8
(C-3), 122.4 (C-6), 124.7, 125.3, 125.5, 126.1, 139.6 (C-5),
139.7, 140.9, 170.3 and 172.4 (2 × CH3CO) ppm. EI-MS
m/z (relative intensity): 476 (28), 475 (M+, 86), 433 (25),
416 (34), 415 ([M − AcOH]+, 100), 373 (70).
8a (116 mg, 0.25 mmol) was hydrolyzed by general
procedure B. Column chromatography on silica gel with
tert-butyl methyl ether/dichloromethane (20:80 v/v) af-
forded 8b (67 mg, 63%), mp 125–127 ◦C, Rf = 0.3 (ss
D), [α]2D0 = −34. (Found C, 79.82; H, 9.45; N, 3.45.
C28H39NO2 requires C, 79.76; H, 9.32; N, 3.32%); 1H
NMR: δ = 0.83 (s, 3H, 18-H3), 1.03 (s, 3H, 19-H3),
0.98–1.13 (m, 2H), 1.31 (d, J = 6.9 Hz, 3H, 21-H3),
1.29–1.39 (m, 2H), 1.42–1.68 (m, 8H), 1.80–1.88 (m, 2H),
1.94–2.03 (m, 2H), 2.19–2.34 (m, 2H), 3.04 (m, 1H, 20-H),
3.40 (m, 1H, 16-H), 3.51 (m, 3H), 3.74 (s, 3H, O-CH3),
5.35 (m, 1H, 6-H), 6.56 (d, J = 8.5 Hz, 1H, 6ꢀ-H), 6.61
(dd, J = 8.5, 2.8 Hz, 1H, 5ꢀ-H), 6.81 (d, J = 2.8 Hz,
1H, 3ꢀ-H) ppm. 13C NMR: δ = 12.7, 19.3, 19.4, 20.5,
30.6, 31.6, 31.6, 31.6, 34.5, 36.5, 37.2, 39.0, 42.0, 42.3,
50.4, 55.2, 55.7, 57.2, 59.7, 71.6, 112.1, 113.8, 117.5,
121.3 (C-6), 131.6, 140.2, 141.0 (C-5), 153.0 ppm. EI-MS
m/z (relative intensity): 422 (30), 421 (M+, 100), 404
(6).

A. Magyar et al. / Steroids 69 (2004) 301–312
305
2.1.12. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-acetoxy-1ꢀ-acetyl-6ꢀ-
methoxy-4ꢀ-methyl-(16β,17α)-androsta-5,16-dieno[17,
16-b]quinoline (8c)
21-H3), 1.24–1.38 (m, 2H), 1.43–1.68 (m, 8H), 1.84 (m,
2H), 1.93–2.03 (m, 2H), 2.20–2.33 (m, 2H), 3.03 (m, 1H,
20-H), 3.43 (m, 1H, 16-H), 3.52 (m, 1H, 3-H), 5.35 (m, 1H,
6-H), 6.45 (d, J = 8, 7 Hz, 1H, 6ꢀ-H), 7.05 (dd, J = 8.7,
8a (464 mg, 1.0 mmol) was acetylated by the general
procedure C. Recrystallization from methanol afforded 8c
2.3 Hz, 1H, 5ꢀ-H), 7.30 (d, J = 2.3 Hz, 1H, 3ꢀ-H) ppm. 13
C
(396 mg, 78%), mp 206–209 ◦C, Rf = 0.2 (ss A), [α]20
=
NMR: δ = 12.6, 19.0, 19.4, 20.5, 27.0, 30.4, 31.6, 34.4,
36.5, 37.2, 38.9, 42.0, 50.4, 55.3, 56.8, 58.8, 58.9, 71.6,
110.6, 117.8, 121.2 (C-6), 129.2, 130.8, 132.1, 141.0 (C-5),
145.5 ppm. EI-MS m/z (relative intensity): 472 (28), 471
([M + 2]+, 100), 470 (35), 469 (M+, 100).
2.1.15. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-acetoxy-1ꢀ-acetyl-6ꢀ-
bromo-4ꢀ-methyl-(16β,17α)-androsta-5,16-dieno[17,
16-b]quinoline (9c)
+106. (Found C, 75.87; H, 8.68; N, 2.90. C32H43NOD4 re-
1
quires C, 76.00; H, 8.57; N, 2.77%); H NMR: δ = 0.87
(s, 3H, 18-H3), 1.04 (s, 3H, 19-H3), 0.97–1.08 (m, 1H),
1.13 (m, 1H), 1.33 (d, J = 6.9 Hz, 3H, 21-H3), 1.24–1.36
(m, 1H), 1.40 (t, J = 11.2 Hz, 1H), 1.46–1.65 (m, 6H),
2.03 (s, 3H, CH3COO), 1.73–2.06 (m, 5H), 2.15 (s, 3H,
CH3CON), 2.27–2.38 (m, 3H), 2.84 (m, 1H, 20-H), 3.81 (s,
3H, O-CH3), 3.77–3.88 (m, 1H, 16-H), 4.60 (m, 1H, 3-H),
5.37 (m, 1H, 6-H), 6.69 (dd, J = 8.7, 2.8 Hz, 1H, 5ꢀ-H),
6.79 (d, J = 2.8 Hz, 1H, 3ꢀ-H), 7.09 (d, J = 8.7 Hz, 1H,
6ꢀ-H) ppm. 13C NMR: δ = 12.9, 18.2, 19.2, 20.3, 21.3, 24.7,
27.6, 29.5, 31.3, 31.4, 35.7, 36.6, 36.8, 38.0, 38.4, 40.5,
50.1, 55.3, 55.8, 60.5, 64.4, 73.8, 110.0, 112.4, 122.5 (C-6),
126.0, 134.3, 139.5 (C-5), 141.2, 156.7, 170.4 (CH3COO),
172.6 (CH3CON) ppm. EI-MS m/z (relative intensity): 506
(36), 505 (M+, 100), 463 ([M + H − Ac]+, 24).
9a (523 mg, 1.0 mmol) was acetylated by the general pro-
cedure C. Column chromatography on silica gel with ethyl
acetate/dichloromethane (5:95 v/v) afforded 9c (427 mg,
77%), mp 218–220 ◦C, Rf = 0.6 (ss A), [α]2D0 = −113.
(Found C, 67.32; H, 7.34; N, 2.30. C31H40BrNO3 requires
1
C, 67.14; H, 7.27; N, 2.53%); H NMR: δ = 0.89 (s, 3H,
18-H3), 1.04 (s, 3H, 19-H3), 0.98–1.07 (m, 1H), 1.13 (td,
J = 13.9, 4.1 Hz, 1H), 1.34 (d, J = 6.9 Hz, 3H, 21-H3),
1.24–1.38 (m, 2H), 1.42–1.62 (m, 6H), 1.80–1.90 (m, 3H),
2.03 (s, 3H, CH3COO), 1.91–2.05 (m, 2H), 2.17 (s, 3H,
CH3CON), 2.14–2.24 (m, 1H), 2.28–2.36 (m, 2H), 2.84
(dq, J = 10.5, 6.9 Hz, 1H, 20-H), 3.88 (td, J = 11.0,
5.9 Hz, 1H, 16-H), 4.60 (m, 1H, 3-H), 5.37 (m, 1H, 6-H),
7.09 (d, J = 7.9 Hz, 1H, 6ꢀ-H), 7.28 (dd, J = 7.9, 1.8 Hz,
1H, 5ꢀ-H), 7.35 (d, J = 1.8 Hz, 1H, 3ꢀ-H) ppm. 13C NMR:
δ = 12.8, 17.4, 19.2, 20.3, 21.3, 24.6, 27.6, 30.2, 31.2, 31.3,
35.7, 36.5, 36.8, 38.0, 38.4, 40.5, 50.1, 55.9, 60.3, 64.2, 73.7
(C-3), 117.9, 122.3 (C-6), 126.7, 128.4, 128.9, 139.5, 139.6
(C-5), 141.9, 170.4 (CH3COO), 172.2 (CH3CON) ppm.
EI-MS m/z (relative intensity): 556 (20), 555 ([M + 2]+,
70), 554 (20), 553 (M+, 66), 496 (30), 495 (98), 494 (32),
493 ([M − AcOH]+, 100), 454 (14), 455 (58), 452 (30),
451 (62), 210 (15), 208 (13), 157 (16), 43 (28).
2.1.13. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-hydroxy-1ꢀ-acetyl-6ꢀ-
methoxy-4ꢀ-methyl-(16β,17α)-androsta-5,16-dieno[17,
16-b]quinoline (8d)
8c (126 mg, 0.25 mmol) was hydrolyzed by general pro-
cedure B. Recrystallization from dichloromethane/light
petroleum afforded flat crystals 8d (90 mg, 78%). mp
230–234 ◦C, Rf = 0.4 (ss H), [α]2D0 = −111. (Found C,
77.85; H, 9.05; N, 2.96. C30H41NO3 requires C, 77.71; H,
1
8.91; N 3.02%); H NMR: δ = 0.89 (s, 3H, 18-H3), 1.03
(s, 3H, 19-H), 0.95–1.14 (m, 2H), 1.33 (d, J = 6.4 Hz,
3H, 21-H3), 1.22–1.36 (m, 1H), 1.41 (t, J = 11.2 Hz, 1H),
1.45–1.66 (m, 6H), 1.70–1.88 (m, 3H), 1.90–2.04 (m, 2H),
2.14 (s, 3H, CH3CO), 2.18–2.34 (m, 2H), 2.34–2.42 (m,
1H), 2.85 (m, 1H, 20-H), 3.52 (m, 1H, 3-H), 3.80 (s, 3H,
OMe), 3.75–3.86 (m, 1H, 16-H), 5.35 (m, 1H, 6-H), 6.69
(dd, J = 8.7, 2.4 Hz, 1H, 5ꢀ-H), 6.79 (d, J = 2.4 Hz, 1H,
3ꢀ-H), 7.08 (d, J = 8.7 Hz, 1H, 6ꢀ-H) ppm. 13C NMR:
δ = 12.9, 18.6, 19.4, 20.5, 24.7, 29.4, 31.4, 31.5, 31.6, 35.7,
36.5, 37.1, 38.6, 40.7, 42.3, 50.4, 55.4, 55.9, 60.7, 64.7,
71.6 (C-3), 110.l, 112.7, 121.5 (C-6), 126.1, 134.5, 140.7
(C-5), 141.2, 156.9, 172.7 (CH3CO). EI-MS m/z (relative
intensity): 464 (30), 463 (M+, 100), 42l (20).
2.1.16. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-hydroxy-1ꢀ-acetyl-6ꢀ-
bromo-4ꢀ-methyl-(16β,17α)-androsta-5,16-dieno[17,
16-b]quinoline (9d)
9c (136 mg, 0.25 mmol) was hydrolyzed by general proce-
dure B. Recrystallization from dichloromethane/petrolether
afforded 9d (109 mg, 85%), mp 211–214 ◦C, Rf = 0.4 (ss
E), [α]2D0 = −113. (Found C, 68.05; H, 7.62; N, 2.95.
1
C29H38BrNO2 requires C, 67.96, H, 7.47; N, 2.73%); H
2.1.14. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-hydroxy-6ꢀ-bromo-4ꢀ-
methyl-(16β,17α)-androsta-5,16-dieno[17,16-b]quinoline
(9b)
NMR: δ = 0.89 (s, 3H, 18-H3), 1.03 (s, 3H, 19-H3), 1.34 (d,
J = 6.9 Hz, 3H, 21-H3), 2.17 (s, 3H, CH3CO), 0.94–2.35
(m, 18H), 2.84 (m, 1H, 20-H), 3.52 (m, 1H, 3-H), 3.88 (td,
J = 11.0, 6.0 Hz, 1H, 16-H), 5.34 (m, 1H, 6-H), 7.09 (d,
J = 8.7 Hz, 1H, 6ꢀ-H), 7.28 (d, J = 8.7 Hz, 1H, 5ꢀ-H),
7.35 (s, 1H, 3ꢀ-H) ppm. 13C NMR: δ = 12.8, 17.5, 19.3,
20.4, 24.7, 30.2, 31.3, 31.4, 31.5, 35.7, 36.5, 37.1, 38.5,
40.6, 42.2, 50.3, 56.0, 60.3, 64.3, 71.6 (C-3), 118.0, 121.4
(C-6), 126.7, 128.5, 129.1, 139.6, 140.7 (C-5), 142.0, 172.3
(CH3CO) ppm. EI-MS m/z (relative intensity): 514 (26), 513
9a (128 mg, 0.25 mmol) was hydrolyzed by general
procedure B. Recrystallization from acetone afforded 9b
(108 mg, 92%) as clear white crystals. mp 245–247 ◦C,
Rf = 0.3 (ss E), [α]2D0 = +74. (Found C, 69.05; H,
7.65; N, 3.06. C27H36BrNO requires C, 68.93; H, 7.71;
1
N, 2.98%); H NMR: δ = 0.83 (s, 3H, 18-H3), 1.04 (s,
3H, 19-H3), 0.98–1.13 (m, 2H), 1.30 (d, J = 6.4 Hz, 3H,

306
A. Magyar et al. / Steroids 69 (2004) 301–312
1
([M+2]+, 100), 512 (28), 511 (M+, 96), 471 (48), 469 (46),
433 (16), 255 (16), 251 (18), 156 (24), 91 (58), 83 (40), 57
(32), 43 (22).
N, 5.85%); H NMR: δ = 0.95 (s, 3H, 18-H3), 1.03 (s,
3H, 19-H3), 1.42 (d, J = 6.9 Hz, 3H, 21-H3), 1.82 (d,
J = 10.1 Hz, 2H), 2.26 (s, 3H, CH3CON), 2.89 (m, 1H,
20-H), 3.51 (m, 1H, 3-H), 4.04 (m, 1H, 16-H), 5.34 (m, 1H,
6-H), 7.47 (d, J = 8.7 Hz, 1H, 6ꢀ-H), 8.04 (d, J = 8.7 Hz,
1H, 5ꢀ-H), 8.11 (s, 1H, 3ꢀ-H) ppm. 13C NMR: δ = 12.8,
16.4, 19.4, 20.3, 24.9, 31.3, 31.5, 31.6, 31.6, 35.9, 36.6,
37.1, 38.6, 40.6, 42.3, 50.4, 56.1, 60.2, 64.2, 71.6 (C-3),
120.85, 121.1, 121.3, 125.1, 140.6, 141.0, 143.9, 145.5,
172.0 (CH3CON) ppm. EI-MS m/z (relative intensity): 478
(M+, 100), 436 ([M − Ac]+, 85).
2.1.17. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-hydroxy-6ꢀ-nitro-4ꢀ-
methyl-(16β,17α)-androsta-5,16-dieno[17,16-b]quinoline
(10b)
10a (120 mg, 0.25 mmol) was hydrolyzed by general pro-
cedure B. Recrystallization from methanol afforded 10b
(87 mg, 79%), mp 162–165 ◦C, Rf = 0.6 (ss D), [α]20
=
+217. (Found C, 74.46; H, 8.45; N, 6.58. C27H36N2OD3 re-
quires C, 74.28, H, 8.31; N, 6.42%); 1H NMR: δ = 0.85 (s,
3H, 18-H3), 1.04 (s, 3H, 19-H3), 0.97–1.14 (m, 2H), 1.37
(d, J = 6.4 Hz, 3H, 21-H3), 1.28–1.40 (m, 2H), 1.42–2.35
(m, 15H), 3.05 (m, 1H, 20-H), 3.52 (m, 1H, 3-H), 3.59 (m,
1H, 16-H), 4.81 (br s, 1H, N-H), 5.34 (m, 1H, 6-H), 6.46
(d, J = 9.2 Hz, 1H, 6ꢀ-H), 7.87 (dd, J = 9.2, 2.3 Hz, 1H,
5ꢀ-H), 8.12 (d, J = 2.3 Hz, 3ꢀ-H) ppm. 13C NMR: δ = 12.4,
18.1, 19.4, 20.4, 30.0, 31.5, 31.5, 31.6, 34.5, 36.5, 37.1, 38.8,
41.9, 42.2, 50.3, 55.6, 56.4, 57.8, 71.6 (C-3), 114.1, 121.1
(C-6), 123.6, 124.7, 128.3, 138.6, 141.1 (C-5), 152.1 ppm.
EI-MS m/z (relative intensity): 436 (M+, 100).
2.1.20. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-hydroxy-4ꢀ-methyl-
(16α,17α)-androsta-5,16-dieno[17,16-b]quinoline (11b)
11a (108 mg, 0.25 mmol) was hydrolyzed by general pro-
cedure B. Column chromatography on silica gel with ethyl
acetate/dichloromethane (10:90 v/v) afforded 11b (70 mg,
71%), mp 175–176 ◦C, Rf = 0.2 (ss A), [α]2D0 = −95.
(Found C, 82.95; H, 9.31; N, 3.72. C27H37NO requires C,
82.81; H, 9.52; N 3.58%); 1H NMR: δ = 0.82 (s, 3H,
18-H3), 1.02 (s, 3H, 19-H3), 0.93–1.14 (m, 3H), 1.34 (d,
J = 6.9 Hz, 3H, 21-H3), 1.15–1.37 (m, 2H), 1.44–1.66 (m,
7H), 1.80–1.89 (m, 2H), 1.93 (d, J = 12.3 Hz, 1H), 2.02
(m, 1H), 2.14 (m, 1H), 2.18–2.33 (m, 2H), 2.72 (m, 1H,
20-H), 3.51 (m, 1H, 3-H), 3.63 (m, 1H, 16-H), 5.35 (m,
1H, 6-H), 6.49 (d, J = 7.6 Hz, 1H, 6ꢀ-H), 6.71 (t, J =
7.6 Hz, 1H, 4ꢀ-H), 6.97 (t, J = 7.6 Hz, 1H, 5ꢀ-H), 7.09 (d,
J = 7.6 Hz, 1H, 3ꢀ-H) ppm. 13C NMR: δ = 14.8, 19.4,
20.8, 21.1, 29.7, 31.2, 31.7, 32.0, 35.5, 36.7, 37.3, 39.5,
42.3, 43.1, 50.4, 54.1, 54.7, 58.8, 71.7 (C-3), 113.8, 118.3,
121.4 (C-6), 126.2, 126.3, 130.3, 141.0 (C-5), 146.0 ppm.
EI-MS m/z (relative intensity): 392 (30), 391 (M+, 100), 130
(18).
2.1.18. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-acetoxy-1ꢀ-acetyl-6ꢀ-
nitro-4ꢀ-methyl-(16β,17α)-androsta-5,16-dieno[17,
16-b]quinoline (10c)
10a (479 mg, 1.0 mmol) was acetylated by general proce-
dure C. Column chromatography on silica gel with tert-butyl
methyl ether/light petroleum (1:1 v/v) afforded 10c (427 mg,
82%), mp 212–214 ◦C, Rf = 0.3 (ss C), [α]20 = −268.
(Found: C, 51.68; H, 7.92; N, 5.48. C31H40N2DO5 requires
1
C, 71.51; H, 7.74; N, 5.38%); H NMR: δ = 0.96 (s, 3H,
18-H3), 1.05 (s, 3H, 19-H3), 1.44 (d, J = 6.8 Hz, 3H,
21-H3), 2.03 (s, 3H, CH3COO), 2.27 (s, 3H, CH3CON),
2.33 (m, 2H, 4-H2) 2.90 (m, 1H, 20-H), 4.06 (m, 1H, 16-H),
4.59 (m, 1H, 3-H), 5.37 (m, 1H, 6-H), 7.47 (d, J = 8.9 Hz,
1H, 6ꢀ-H), 8.05 (dd, J = 8.9, 2.2 Hz, 1H, 5ꢀ-H), 8.11 (d,
J = 2.2 Hz, 1H, 3ꢀ-H) ppm. 13C NMR: δ = 12.7, 16.4, 19.3,
20.3, 21.3, 24.9, 27.7, 31.3, 31.4, 31.6, 35.9, 36.6, 36.9, 38.1,
38.6, 40.6, 50.3, 56.0, 60.2, 64.1, 73.7 (C-3), 120.8, 121.4,
122.1, 125.1, 139.9, 140.6, 143.9, 145.5, 170.4, 172.0 (2 ×
CH3CO) ppm. EI-MS m/z (relative intersity): 520 (M+, 5),
490 (8), 461 ([M − AcO]+, 33), 460 ([M − AcOH]+, 100),
418 (30), 253 (10).
2.1.21. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-acetoxy-1ꢀ-acetyl-4ꢀ-
methyl-(16α,17α)-androsta-5,16-dieno[17,16-b]quinoline
(11c)
11a (434 mg, 1.0 mmol) was acetylated by general
procedure C. Recrystallization from methanol afforded
11c (423 mg, 89%), mp 277–279 ◦C, Rf = 0.1 (ss A),
[α]2D0 = +181. (Found C, 78.37; H, 8.76; N, 3.12.
C31H41NO3 requires C, 78.28; H, 8.69; N 2.94%); 1H
NMR: δ = 0.09 (s, 3H, 18-H3), 0.93 (s, 3H, 19-H3),
0.90–1.06 (m, 3H), 1.12 (m, 2H), 1.20 (d, J = 7.3 Hz,
3H, 21-H3), 1.35–1.46 (m, 2H), 1.48–1.62 (m, 3H),
1.77–1.97 (m, 4H), 2.01 (s, 3H, CH3COO), 2.12 (s, 3H,
CH3CON), 2.06–2.36 (m, 4H), 2.86 (q, J = 7.3 Hz,
1H, 20-H), 4.58 (m, 1H, 3-H), 5.22 (m, 1H, 16-H), 5.33
(m, 1H, 6-H), 6.99 (d, J = 6.9 Hz, 1H), 7.07–7.21 (m,
3H) ppm. 13C NMR: δ = 14.9 (C-18), 19.1 (C-19), 20.4,
21.4 (CH3COO), 22.2 (C-21), 22.8 (CH3CON), 27.8,
30.2, 32.1, 32.8, 33.5, 36.7, 36.9, 38.0, 38.8, 43.1, 49.9,
53.6, 54.9, 58.5, 73.8 (C-3), 122.4 (C-6), 126.1, 126.1
(2C), 128.9, 137.7, 139.6 (C-5), 140.7, 170.0 and 170.4
(2 × CH3CO). EI-MS m/z (relative intensity): 475 (M+,
42), 416 (30), 415 ([M − AcOH]+, 100), 373 (22), 130
2.1.19. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-hydroxy-1ꢀ-acetyl-6ꢀ-
nitro-4ꢀ-methyl-(16β,17α)-androsta-5,16-dieno[17,
16-b]quinoline (10d)
10c (130 mg, 0.25 mmol) was hydrolyzed by general
procedure B, resulting in a mixture of 10b and 10d. Col-
umn chromatography on silica gel with tert-butyl methyl
ether/dichloromethane (10:90 v/v) afforded 10b (96 mg,
80%, Rf = 0.5 (ss H)) and 10d (11 mg, 9%). 10b proved to
be identical to that mentioned above. 10d mp 268–270 ◦C,
Rf = 0.3 (ss H), [α]2D0 = +245. (Found C, 72.85, H,
7.93; N, 5.98. C29H38N2O4 requires C, 72.77; H, 8.00;

A. Magyar et al. / Steroids 69 (2004) 301–312
307
(18). Crystal data: C31H41NO3, Mr = 475.65, monoclinic,
2.1.24. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-acetoxy-1ꢀ-acetyl-6ꢀ-
methoxy-4ꢀ-methyl-(16α,17α)-androsta-5,16-dieno[17,
16-b]quinoline (12c)
space group P21, a = 10.807(2) Å, b = 7.3619(15) Å,
c = 16.965(3) Å, β = 101.49(3)◦, V = 1322.6(5) Å3,
Z = 2, ρcalc = 1.194 g cm−3, F(000) = 516, µ(Mo K␣) =
0.075 cm−1, min/max transmission 0.9421/0.9704, crys-
12a (464 mg, 1.0 mmol) was acetylated by general pro-
cedure C. Column chromatography on silica gel with ethyl
acetate/dichloromethane (20:80 v/v) afforded 12c (420 mg,
83%), mp 180–184 ◦C, Rf = 0.1 (ss A), [α]2D0 = +142.
(Found C, 76.22; H, 8.72; N, 2.95. C32H43NO4 requires
tal dimensions 0.8 mm × 0.6 mm × 0.2 mm, 1.92◦
<
Θ < 24.71◦, 10,103 reflections were collected, of which
2441 were independent (Rint = 0.1381) and 2441 were
used for refinement. For the final refinement of 321 pa-
rameters, one restraint was used. The R-values were:
R1 = Σ|Fo − Fc|/ΣFo = 0.0491 for I > 2σ(I),
1
C, 76.00; H, 8.57; N, 2.77%); H NMR: δ = 0.14 (s, 3H,
18-H3), 0.94 (s, 3H, 19-H3), 0.90–1.03 (m, 3H), 1.06–1.16
(m, 2H), 1.19 (d, J = 7.3 Hz, 3H, 21-H3), 1.33–1.47 (m,
2H), 1.47–1.61 (m, 3H), 1.76–1.97 (m, 4H), 2.02 (s, 3H,
CH3COO), 2.08 (s, 3H, CH3CON), 1.99–2.10 (m, 1H),
2.13–2.35 (m, 3H), 2.81 (q, J = 7.3, 1H, 20-H), 3.80
(s, 3H, O-CH3), 4.58 (m, 1H, 3-H), 5.22 (m, 1H, 16-H),
5.34 (m, 1H, 6-H), 6.66 (d, J = 2.8 Hz, 1H, 3ꢀ-H), 6.71
(dd, J = 8.5, 2.8 Hz, 1H, 5ꢀ-H), 6.91 (d, J = 8.5 Hz, 1H,
6ꢀ-H) ppm. 13C NMR: δ = 14.9, 19.1, 20.4, 21.4, 22.1, 22.7,
27.7, 30.2, 32.0, 32.6, 33.9, 36.7, 36.8, 38.0, 38.8, 43.1,
49.9, 53.4, 54.7, 55.4, 57.7, 73.8 (C-3), 111.2, 114.0, 122.4
(C-6), 126.9, 130.7, 139.6 (C-5), 142.1, 157.8, 170.0 and
170.4 (CH3COO and CH3CON) ppm. EI-MS m/z (relative
intensity): 506 (35), 505 (M+, 100).
ꢀ
ꢀ
and wR2 = [ w(Fo2 − Fc2)2/ wFo4]1/2 = 0.1126
for all data; max/min residual electron density: 0.18/−
0.19 eÅ−3
.
2.1.22. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-hydroxy-1ꢀ-acetyl-4ꢀ-
methyl-(16α,17α)-androsta-5,16-dieno[17,16-b]quinoline
(11d)
11c (119 mg, 0.25 mmol) was hydrolyzed by general pro-
cedure B. Column chromatography on silica gel with ethyl
acetate/dichloromethane (30:70 v/v) afforded 11d (73 mg,
67%), mp 287–290 ◦C, Rf = 0.3 (ss H), [α]2D0 = +221.
(Found C, 80.54; H, 8.95; N, 3.55. C29H39NO2 requires
1
C, 80.33; H, 9.07; N, 3.23%); H NMR: δ = 0.09 (s, 3H,
2.1.25. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-hydroxy-1ꢀ-acetyl-6ꢀ-
methoxy-4ꢀ-methy-(16α,17α)-androsta-5,16-dieno[17,
16-b]quinoline (12d)
18-H3), 0.92 (s, 3H, 19-H3), 1.20 (d, J = 6.9 Hz, 3H,
21-H3), 2.12 (s, 3H, CH3CO), 0.84–2.32 (m, 18H), 2.86 (m,
1H, 20-H), 3.50 (m, 1H, 3-H), 5.22 (m, 1H, 16-H), 5.30 (m,
1H, 6-H), 6.99 (d, J = 7.3 Hz, 1H, 6ꢀ-H), 7.05–7.21 (m,
3H) ppm. 13C NMR: δ = 14.9, 19.2, 20.4, 22.2, 22.8, 30.2,
31.5, 32.0, 32.7, 33.5, 36.6, 37.2, 38.8, 42.2, 43.1, 50.0,
53.6, 54.9, 58.1, 71.5, 121.3 (C-6), 126.0, 126.1 (2C). 128.8,
137.7, 140.6, 140.8, 169.5 (CH3CO) ppm. EI-MS m/z (rela-
tive intensity): 434 (30), 433 (M+, 100), 391 (22), 390 (15),
130 (15), 106 (10).
12c (126 mg, 0.25 mmol) was hydrolyzed by general pro-
cedure B. Column chromatography on silica gel with ethyl
acetate/dichloromethane (30:70 v/v) afforded 12d (81 mg,
70%), mp 255–256 ◦C, Rf = 0.3 (ss D), [α]2D0 = +177.
(Found C, 77.85; H, 9.02; N, 2.96. C30H41NO3 requires
1
C, 77.71; H, 8.91; N, 3.02%); H NMR: δ = 0.14 (s, 3H,
18-H3), 0.92 (s, 3H, 19-H3), 1.19 (d, J = 7.3 Hz, 3H,
21-H3), 2.08 (s, 3H, CH3CO), 0.84–2.35 (m, 15H), 2.82 (q,
J = 7.3 Hz, 1H, 20-H), 3.50 (m, 1H, 3-H), 3.79 (s, 3H,
O-CH3), 5.22 (m, 1H, 16-H), 5.31 (m, 1H, 6-H), 6.67 (s,
1H, 3ꢀ-H), 6.71 (d, J = 8.7 Hz, 1H, 5ꢀ-H), 6.91 (d, J =
8.7 Hz, 1H, 5ꢀ-H) ppm. 13C NMR: δ = 14.9, 19.2, 20.4,
22.1, 22.7, 30.2, 31.5, 32.0, 32.5, 33.9, 36.6, 37.2, 38.9, 42.2,
43.1, 50.1, 53.5, 54.7, 55.4, 57.7, 71.5 (C-3), 111.2, 114.1,
121.3 (C-6), 126.9, 130.6, 140.8 (C-5), 142.1, 157.8, 170.0
(CH3CO) ppm. EI-MS m/z (relative intensity): 464 (30), 463
(M+, 100), 421 (16), 160 (10).
2.1.23. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-hydroxy-6ꢀ-methoxy-4ꢀ-
methyl-(16α,17α)-androsta-5,16-dieno[17,16-b]quinoline
(12b)
12a (116 mg, 0.25 mmol) was hydrolyzed by general
procedure B. Recrystallization from dichloromethane/light
petroleum afforded 12b (100 mg, 95%), mp 220–223 ◦C,
Rf = 0.2 (ss A), [α]2D0 = −95. (Found: C, 79.89; H,
9.46; N, 3.45. C28H39NO2 requires C, 79.76; H, 9.32; N,
1
3.32%); H NMR: δ = 0.89 (s, 3H, 18-H3), 1.03 (s, 3H,
19-H3), 0.94–1.16 (m, 3H), 1.17–l.33 (m, 2H), 1.35 (d,
J = 6.9 Hz, 3H, 21-H3), 1.44–1.68 (m, 6H), 1.80–l.89
(m, 2H), 1.92–2.12 (m, 3H), 2.18–2.33 (m, 2H), 2.71 (m,
1H, 20-H), 3.46–3.57 (m, 2H, 3-H and 16-H), 3.75 (s,
3H, O-CH3), 5.35 (m, 1H, 6-H), 6.48 (d, J = 8.4 Hz,
1H, 6ꢀ-H), 6.58 (dd, J = 8.4, 2.6 Hz, 1H, 5ꢀ-H), 6.76
(d, J = 2.6, 1H, 3ꢀ-H) ppm. 13C NMR: δ = 15.2, 19.3,
19.4, 20.8, 30.1, 31.2, 31.6, 32.1, 34.6, 36.6, 37.3, 39.9,
42.3, 43.1, 50.3, 54.4, 55.8, 56.1, 59.3, 71.7, 110.7, 112.5,
114.5, 121.3 (C-6), 133.2, 140.9, 141.0 (C-5), 153.1 ppm.
EI-MS m/z (relative intensity): 422 (30), 421 (M+, 100),
160 (12).
2.1.26. 1ꢀ,4ꢀ,16,17-tetrahydro-3β-hydroxy-6ꢀ-bromo-4ꢀ-
methyl-(16α,17α)-androsta-5,16-dieno[17,16-b]quinoline
(13b)
13a (128 mg, 0.25 mmol) was hydrolyzed by general pro-
cedure B. Column chromatography on silica gel with ethyl
acetate/dichloromethane (10:90 v/v) afforded 13b (98 mg,
83%), mp 226–228 ◦C, Rf = 0.2 (ss A), [α]2D0 = −98.
(Found C, 69.05; H, 7.80; N, 3.10. C27H36BrNO requires
C, 68.93; H, 7.71; N, 2.98%); 1H NMR (500 MHz, DMSO):
δ = 0.64 (s, 3H, 18-H3), 0.94 (s, 3H, 19-H3), 1.20 (d, J =
5.0 Hz, 3H, 21-H3), 0.75–1.27 (m, 6H), 1.27–1.86 (m, 9H),

308
A. Magyar et al. / Steroids 69 (2004) 301–312
1.86–2.00 (m, 1H), 2.01–2.26 (m, 3H), 2.63 (m, 1H, 20-H),
3.25 (m, 1H, 3-H), 3.58 (m, 1H, 16-H), 4.60 (d, J = 4.6 Hz,
1H, OH), 5.27 (m, 1H, 6-H), 5.69 (s, 1H, NH), 6.42 (d,
J = 7.3 Hz, 1H, 6ꢀ-H), 6.94 (d, J = 6.9 Hz, 1H, 5ꢀ-H), 7.04
(s, 1H, 3ꢀ-H) ppm. 13C NMR (75 MHz, DMSO): δ = 14.0,
19.1, 20.1, 23.0, 28.9, 30.7, 31.3 (2C), 35.5, 36.1, 36.9, 38.2,
42.1, 42.4, 49.9, 51.0, 54.2, 56.4, 69.9, 106.4, 114.8, 120.16,
128.3, 128.8, 129.9, 141.3, 144.9 ppm. EI-MS m/z (relative
intensity): 472 (30), 471 ([M+2]+, 95), 470 (30), 469 (M+,
100).
2.1.29. 3β-Hydroxy-16β-[N-(4ꢀ-nitro)phenyl]amino-17a␤-
fluoro-17␣-methyl-d-homo-androst-5-ene (14b)
14a (125 mg, 0.25 mmol) was hydrolyzed by general pro-
cedure B. Column chromatography on silica gel with ethyl
acetate/dichloromethane (10:90 v/v) afforded 14b (95 mg,
83%) mp 262–264 ◦C, Rf = 0.4 (ss F), [α]2D0 = +47. (Found
C, 70.96; H, 8.35; N, 6.25. C27H37FN2O3 requires C, 71.02;
1
H, 8.17; N, 6.14%); H NMR: δ = 0.94 (s, 3H, 18-H3),
1.00 (s, 3H, 19-H3), 1.12 (d, J = 5.5 Hz, 3H, 21-H3), 3.07
(qd, J = 10.3, 4.6 Hz, 1H, 17-H), 3.53 (m, 1H, 3-H), 3.74
(dd, J = 47.9, 10.3 Hz, 1H, 17a-H), 4.29 (d, J = 9.2 Hz,
1H, 16-H), 5.31 (m, 1H, 6-H), 6.50 (d, J = 9.2 Hz, 2H, 2ꢀ-
and 6ꢀ-H), 8.08 (d, J = 9.2 Hz, 2H, 3ꢀ- and 5ꢀ-H) ppm. 13C
NMR: δ = 11.9, 15.1, 19.3, 19.6, 30.6, 30.8, 31.6, 31.9,
36.6, 36.8, 36.9, 38.0 (d, J = 17.1 Hz, C-13), 39.3 (d, J =
18.9 Hz, C-17), 42.0, 46.0 (d, J = 5.4 Hz), 49.6, 56.1 (d,
J = 11.7 Hz), 71.6 (C-3), 103.2 (d, J = 183.7 Hz, C-17a),
111.1 (2C, C-2ꢀ and -6ꢀ), 120.7 (C-6), 126.7 (2C, C-3ꢀ and
-5ꢀ), 138.0 (C-4ꢀ), 140.7 (C-5), 152.9 (C-1ꢀ) ppm. EI-MS m/z
(relative intensity): 456 (M+, 100).
2.1.27. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-acetoxy-1ꢀ-acetyl-6ꢀ-
bromo-4ꢀ-methyl-(16α,17α)-androsta-5,16-dieno[17,
16-b]quinoline (13c)
13a (513 mg, 1.0 mmol) was acetylated by general pro-
cedure C. Column chromatography on silica gel with ethyl
acetate/dichloromethane (20:80 v/v) afforded 13c (377 mg,
68%), mp 222–225 ◦C, Rf = 0.6 (ss G), [α]2D0 = +154.
(Found C, 67.28; H, 7.35; N, 2.66. C31H40BrNO3 requires
C, 67.14,; H, 7.27; N, 2.53%); 1H NMR: δ = 0.16 (s,
3H, 18-H3), 0.94 (s, 3H, 19-H3), 1.20 (d, J = 7.3 Hz, 3H,
21-H3), 0.88–1.23 (m, 5H), 1.34–1.62 (m, 5H), 1.70–1.97
(m, 4H), 2.02 (s, 3H, CH3COO), 2.11 (br s, 3H, CH3CON),
1.98–2.39 (m, 4H), 2.83 (q, J = 7.3 Hz, 1H, 20-H), 4.58
(m, 1H, 3-H), 5.19 (m, 1H, 16-H), 5.34 (m, 1H, 6-H), 6.87
(m, 1H, 6ꢀ-H), 7.19–7.34 (m, 2H, 3ꢀ- and 5ꢀ-H) ppm. 13C
NMR (125 MHz, CDCl3): δ = 15.2, 19.1, 20.3, 21.4, 21.9,
22.8, 27.6, 30.1, 32.0, 32.9, 33.4, 36.6, 36.8, 38.0, 38.6,
43.1, 49.8, 53.5, 54.9, 57.8, 73.7 (C-3), 119.1, 122.3 (C-6),
127.4, 129.2, 131.5, 136.8, 139.6 (C-5), 142.8, 169.7 and
170.4 (CH3COO and CH3CON) ppm. EI-MS m/z (relative
intensity): 556 (18), 555 ([M+2]+, 52), 554 (18), 553 (M+,
50), 496 ([M + 2 − OAc]+, 30), 495 ([M + 2 − AcOH]+,
100), 494 ([M − OAc]+, 36), 493 ([M − AcOH]+, 96), 453
(25), 45l (22), 224 (18), 222 (16), 210 (24), 208 (22).
2.1.30. 3β-Acetoxy-N-acetyl-16␤-[N-(4ꢀ-nitro)phenyl]
amino-17a␤-fluoro-17␣-methyl-d-homoandrost-5-ene (14c)
14a (113 mg, 0.23 mmol) was dissolved in benzene
(15 ml) in a flask equipped with a solvent trap. Benzene
(4 ml) was distilled off, and isopropenyl acetate (1 ml) and
p-toluenesulfonic acid (5 mg) were then added to the mix-
ture. A further amount of benzene (2 ml) was distilled off
in 1.5 h. Water (20 ml) was added to the solution, and it was
extracted with dichloromethane (3 × 20 ml). The combined
organic phases were washed with aqueous NaHCO3 (20 ml),
dried over anhydrous Na2SO4, and evaporated in vacuo.
The resulting deep-brown substance was chromatographed
on silica gel with tert-butyl ether/dichloromethane (10:90
v/v) yielding pure 14c (109 mg, 89%), mp 226–228 ◦C,
Rf = 0.6 (ss H), [α]2D0 = −49. (Found C, 68.98; H, 7.85; N,
5.30. C31H41FN2O5 requires C, 68.87; H, 7.64; N, 5.18%);
1H NMR: δ = 0.56 (s, 3H, 18-H3), 0.93 (s, 3H, 19-H3),1.18
(d, J = 5.5 Hz, 3H, 21-H3), 2.01 (s, 3H, CH3COO), 3.77
(dd, J = 48.1, 9.6 Hz, 1H, 17a-H), 4.57 (m, 1H, 3-H), 4.67
(m, 1H, 16-H), 5.32 (m, 1H, 6-H), 7.32 (d, J = 8.0 Hz,
2H, 2ꢀ- and 6ꢀ-H), 8.31 (d, J = 8.0 Hz, 3ꢀ- and 5ꢀ-H) ppm.
13C NMR: δ = 11.6, 14.9, 19.1, 19.3, 21.3, 23.4, 27.3,
28.5, 30.9, 31.8, 35.5 (d, J = 19.9 Hz, C-17), 36.2, 36.5,
36.8, 37.6, 37.8, 45.6 (d, J = 5.4 Hz, C-16), 49.2, 55.7,
73.7 (C-3), 103.4 (d, J = 182.8 Hz, C-17a), 121.6 (3C,
C-6 and -2ꢀ and -6ꢀ), 124.8 (2C, C-3ꢀ and -5ꢀ), 139.6 (C-5),
145.2 and 147.5 (C-1ꢀ and -4ꢀ), 169.5 and 170.4 (CH3COO
and CH3CON) ppm. EI-MS m/z (relative intensity): 480
([M − AcOH]+, 100). DCI-MS m/z (relative intensity): 575
([M + NH3 + NH4]+, 16), 558 ([M + NH4]+, 100), 541
([M + H]+, 7). Crystal data: C31H41FN2O5, Mr = 540.66,
orthorhombic, space group P212121, a = 8.1240(10) Å,
b = 14.483(2) Å, c = 24.509(4) Å, V = 2883.7(7) Å3, Z =
4, ρcalc = 1.245 g cm−3, F(000) = 1160, µ(Mo K␣) =
0.718 cm−1, min/max transmission 0.8697/0.9316, crys-
2.1.28. 1ꢀ,4ꢀ,16,17-Tetrahydro-3β-hydroxy-1ꢀ-acetyl-6ꢀ-
bromo-4ꢀ-methyl-(16α,17α)-androsta-5,16-dieno[17,
16-b]quinoline (13d)
13c (136 mg, 0.25 mmol) was hydrolyzed by general pro-
cedure B. Column chromatography on silica gel with ethyl
acetate/dichloromethane (30:70 v/v) afforded 13d (88 mg,
69%), mp 245–251 ◦C, Rf = 0.3 (ss D), [α]2D0 = +155.
(Found C, 67.85; H, 7.65; N, 7.55. C29H38BrNO2 requires
1
C, 67.96; H, 7.47; N, 2.73%); H NMR: δ = 0.16 (s, 3H,
18-H3), 0.93 (s, 3H, 19-H3), 1.19 (d, J = 7.3 Hz, 3H,
21-H3), 2.10 (br s, 3H, NAc), 2.82 (m, 1H, 20-H), 3.50 (m,
1H, 3-H), 5.18 (m, 1H, 16-H), 5.13 (m, 1H, 6-H), 6.86 (m,
1H, 6ꢀ-H), 7.23–7.31 (m, 2H, 3ꢀ- and 5ꢀ-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 15.2, 19.2, 20.3, 21.9, 22.8, 30.1,
31.4, 32.0, 32.8, 33.4, 36.5, 37.1, 38.6, 42.1, 43.1, 50.0, 53.5,
54.9, 57.8, 71.5 (C-3), 119.1, 121.3 (C-6), 127.4, 129.2,
131.5, 136.6, 140.7 (C-5), 142.8, 169.8 (NAc) ppm. EI-MS
m/z (relative intensity): 514 (32), 513 ([M + 2]+, 98), 512
(34), 511 (M+, 100), 471 (26), 469 (28), 224 (14). 222 (16),
210 (18), 43 (20).

A. Magyar et al. / Steroids 69 (2004) 301–312
309
tal dimensions 0.2 mm × 0.2 mm × 0.1 mm, 3.54◦
<
17a-H), 4.67 (m, 1H, 16-H), 5.30 (m, 1H, 6-H), 7.33 (d, J =
8.0 Hz, 2H, 2ꢀ- and 6ꢀ-H), 8.32 (d, J = 8.4 Hz, 2H, 3ꢀ- and
5ꢀ-H) ppm. 13C NMR: δ = 11.7, 15.0, 19.2, 19.4, 23.4, 28.6,
30.9, 31.5, 31.9, 35.6 (d, J = 18.9 Hz, C-17), 36.3, 36.8
(2C), 37.7 (d, J = 16.9 Hz, C-13), 42.0, 45.8, 49.4, 55.8,
71.5 (C-3), 103.5 (d, J = 182.2 Hz, C-17a), 120.7 (3C, C-6
and -2ꢀ and -6ꢀ), 124.8 (2C, C-3ꢀ and 5ꢀ), 140.7 (C-5), 145.2
and 147.6 (C-4ꢀ and C-1ꢀ), 169.6 (CH3CON) ppm. EI-MS
m/z (relative intensity): 498 (M+, 50), 478 ([M−HF]+, 100),
318 (35), 300 (65), 285 (48), 207 (32), 180 (44), 43 (32).
Θ < 59.09◦, 38,005 reflections were collected, of which
4154 were independent (Rint = 0.0240) and 4154 were
used for refinement. For the final refinement of 358 pa-
rameters, no restraints were used. The R-values were:
R1 = Σ|Fo − Fc|/ΣFo = 0.0258 for I > 2σ(I), and
ꢀ
ꢀ
wR2 = [ w(Fo2 − Fc2)2/ wFo4]1/2 = 0.0672 for all
data; max/min residual electron density: 0.19/−0.16 eÅ−3
.
2.1.31. 3β-Hydroxy-N-acetyl-16␤-[N-(4ꢀ-nitro)-phenyl]-
amino-17a␤-fluoro-17␣-methyl-d-homo-androsta-5-ene
(14d)
3. Results and discussion
14c (135 mg, 0.25 mmol) was hydrolyzed by general pro-
cedure B. Recrystallization from methanol afforded 14d
(110 mg, 88%), mp 157–159 ◦C, Rf = 0.3 (ss D), [α]20
=
We recently demonstrated that the d-seco-steroid 2a can
be obtained in five steps from the readily available pregna-
dienolone acetate (1) [6]. The steroidal aldehyde 2b was re-
acted with aniline derivatives 3–6 and subsequently treated
with BF3·OEt2 as a Lewis acid. The reactions resulted in
−45. (Found C, 70.02; H, 7.69; N, 5.71. C29H39FN2OD4 re-
quires C, 69.85; H, 7.88, N, 5.62%); 1H NMR: δ = 0.56 (s,
3H, 18-H3), 0.93 (s, 3H, 19-H3), 1.18 (d, J = 5.9 Hz, 3H,
21-H3), 3.50 (m, 1H, 3-H), 3.77 (dd, J = 48.2, 9.9 Hz, 1H,
Scheme 1. Synthesis of steroidal cyclization products 7–14 from d-seco-pregnene 1.

310
A. Magyar et al. / Steroids 69 (2004) 301–312
Table 1
Products of reactions of 2 with different anilines, and their further deriva-
tives
Entry Substrates Reagent
Products
Ratio Overall
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
2 + 3
2 + 4
2 + 5
2 + 6
7a
BF3·OEt2
7a + 11a
8a + 12a
9a + 13a
6.7:1 91
3.8:1 90
4.8:1 93
10a + 14a 5.9:1 85
KOH/MeOH
7b
8b
9b
10b
11b
12b
13b
14b
7c
70
63
92
79
71
95
83
83
90
78
77
82
89
83
68
–
8a
9a
10a
11a
12a
13a
14a
7a
Ac2O/KOAc
8a
9a
8c
9c
10a
11a
12a
13a
14a
14a
7c
10c
11c
12c
13c
–
Isopropenyl acetate 14c
KOH/MeOH
89
93
78
85
7d
8d
9d
8c
9c
10c
11c
12c
13c
14c
10b + 10d 8.5:1 89
11d
12d
13d
14d
67
70
69
88
Scheme 2. The assumed formation of carbocations 17 and 18 from 2 by
treatment with BF3·OEt2.
the 3-acetoxy steroidal Diels-Alder adducts 7a–13a and the
d-homosteroid 14a (Scheme 1). In the cases of the unsubsti-
tuted aniline (3), p-methoxyaniline (4), and p-bromoaniline
(5), we isolated two isomeric Diels-Alder products: the D/E
ring trans (16␣,17␤; 7a–9a) and cis (16␤,17␤; 11a–13a) di-
astereomers in a ratio of 3.8:1 to 6.7:1 (Table 1, entries 1–3).
The total yield was high (90–93%). The best selectivity was
observed for 7a and 11a (R1 = H, 6.7:1). The reaction of
p-nitroaniline (6) proceeded with an overall yield of 85%,
i.e., lower than for the other three substituents. The corre-
sponding trans product 10a and the product of an aza-Prins
reaction (14a) were obtained in a 5.9:1 ratio.
We assume that the unsaturated aldehyde 2 first condenses
with the aniline (3–6) to yield the imine 15. Treatment of 15
with BF3·OEt2 results in the iminium ion 16, which can sub-
sequently give either 17 or 18 in carbocation form. Carboca-
tion 17 can initiate a Friedel-Crafts alkylation to give the for-
mally hetero Diels-Alder cycloadducts 7a–9a and 11a–13a.
In contrast with the normal Diels-Alder reaction, cycload-
dition of the arylimines follows a two-step ionic reaction
mechanism. The cationic forms 17 and 18 can be in equi-
librium with each other. However, cyclic carbocation 18 can
be stabilized by capture of F−, giving the arylamino fluoride
14a. Due to the electron-withdrawing properties of the nitro
group the aromatic ring is less suitable to participate in the
Friedel-Crafts reaction, allowing hereby the other pathway,
which serves the aza-Prins product (Scheme 2).
The chemoselectivity of these reactions can readily be ex-
plained if these results are compared with previous ones. We
earlier reported on the transformations of the seco-estrone
aldehyde 19 by treatment with aniline and subsequently with
BF3·OEt2 [7]. The aryliminium salts formed yielded either
tetrahydroquinolines condensed to the estrone D ring or
N-arylamino-d-homosteroids, depending on the substituent
on the arylimino group. Using p-nitroaniline (6), we obtained
only the aza-Prins product (Scheme 3). With p-nitroaniline
(6) in the present work, we obtained mainly the tetrahydro-
quinoline condensed steroid (10a); indeed, the condensation
of 2 with the other anilines 3–5 did not give d-homosteroids
at all. This behavior can be explained by the difference in the
alkene moiety. A comparison of the presumed structures 17
and 21 reveals that the resulting carbocation 17 is secondary
in contrast with 21, which is primary. We assume that this
stabilizing effect promotes the Friedel-Crafts reaction.

A. Magyar et al. / Steroids 69 (2004) 301–312
311
Fig. 1. Molecular structure of 7d.
the N,O-diacetyl steroids 7c–13c. The p-nitro-substituted
d-homoandrostane 14a did not react under the latter condi-
tions. The reaction of 14a with isopropenyl acetate in the
presence of a catalytic amount of p-toluenesulfonic acid
gave 14c. On hydrolysis, these N,O-diacetyl compounds
(7c–14c) yielded 3-hydroxy-N-acetyl products 7d–14d. The
O-acetyl group underwent selective hydrolysis, while the
p-nitro-substituted tetrahydroquinolinoandrostane 10c gave
not only the mono hydrolysis product 10d, but also the
aminoalcohol 10b.
The structures of the synthetized compounds were de-
1
termined by means of H and 13C NMR spectroscopy and
NOESY experiments. The starting aldehyde 2b displayed
the 18-CH3 signal at 0.92 ppm [6], while the main product
derivatives 7–10 gave a peak in the interval 0.82–0.96 ppm.
The 18-CH3 signal of the-side product derivatives 11c–13c
Scheme 3. Formation of carbocations 21 and 22.
1
The reactions affording hetero Diels-Alder, but not
aza-Prins adducts (2b and anilines 3–5, entries 1–3), also
yielded two diastereomeric products: the 16␤,17␣ (trans)
and 16␣,17␣ (cis annulation) compounds (Table 1).
The main (trans) product was of the same type as ob-
served exclusively in the estrone series [7,8]. Various in-
vestigations have demonstrated that the diastereoselectivity
can be influenced by numerous factors. Sabitha et al. syn-
thetized octahydroacridines in a similar way, using BiCl3
as a catalyst. They noted that the selectivity depended on
the temperature [9]. Working at 0 ◦C, they obtained trans
and cis adducts with the trans diastereomer (92–100%) as
the main product. At room temperature, these two isomers
were formed in a 1:1 ratio. Kiselyov and co-workers found
that the ratio of the tetrahydrochromano[4,3-b]quinoline di-
astereomers produced during the intramolecular cyclization
of aromatic imines was not influenced by the different sol-
vents (MeCN, THF, or CH2Cl2) or catalysts (Yb(OTf)3 or
TFA) applied, whereas the overall yield did vary [10,11].
Linkert et al. revealed the dependence of the diastereomeric
excess on the catalyzing acid (SnCl4, EtAlCl2 or BF3·OEt2)
[12].
and 11d–13d in the H NMR spectra underwent a strong
upfield shift to 0.09–0.16 ppm. The 1H NMR spectra of
13d, 14c, and 14d exhibited surprisingly broad, insignificant
N-acetyl signals, though the 13C NMR signals were the ex-
pected ones. The configurations of the newly formed stere-
ogenic centers could not be established unambiguously by
NMR methods in all cases. X-ray structure analysis of one
representative of each type of compound helped to solve this
problem. Figs. 1 and 2 depict the crystal structures of a main
(7d) and a side Diels-Alder product (11c), respectively.1
Fig. 3 presents the molecular structure of 14c, showing the
16␤,17␣,17a␤ orientation of the new D ring substituents.
We have prepared new steroid-tetrahydroquinoline hy-
brid molecules via Lewis acid-catalyzed cyclization reac-
tions. We obtained two types of hetero Diels-Alder prod-
ucts: 16,17-trans compounds (7a–10a) as the main product
and 16,17-cis (11a–13a) compounds as side-products (en-
tries 1–4). The cyclization of the p-nitroarylamino salt af-
1
Crystallographic data for the structures in this paper have been de-
posited with the Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC-224298 for 7d, CCDC-225031 for 11c
and CCDC-221793 for 14c. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ,
UK (fax: +44-1223-336-033 or e-mail: deposit@ccdc.cam.ac.uk).
The 3-acetoxy derivatives 7a–14a were transformed by
alkaline hydrolysis to aminoalcohol compounds 7b–14b,
while treatment with acetic acid anhydride/KOAc afforded

312
A. Magyar et al. / Steroids 69 (2004) 301–312
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We gratefully acknowledge financial support from the
Hungarian Scientific Research Fund (OTKA T042673). We
thank Mrs. Györgyi Udvarnoki (University of Göttingen,
Germany) for the mass spectra.