Synthesis of N,N-bis[2-(2-pyridyl)ethyl]amino steroids and related compounds intended as chiral ligands for copper ions

Article abstract of DOI:10.1016/S0957-4166(00)00168-3

Compounds with the N,N-bis[2-(2-pyridyl)ethyl]amino structure (RPY2) are useful tridentate ligands for copper(I) ions, which can bind and activate oxygen from the atmosphere. For diastereoselective and enantioselective oxidation reactions, hitherto unknown chiral ligands possessing tripodal structures have been synthesized starting from homochiral steroids. The double Michael addition of primary steroidal amines and aminoalcohols to 2-vinyl pyridine was not very succesful. However, homochiral bidentate ligands with N-[2-(2-pyridyl)ethyl]amino steroid structure could be obtained by this procedure in most cases. New routes (acylation of the bidentate ligands with 2-pyridylacetic acid followed by BH₃.THF reduction, or reductive amination of steroidal ketones, acylation and borane reduction) to the desired tridentate RPY2, also at sterically hindered positions, are described. In the last reaction sequence, 'mixed' tridentate ligands can also be obtained. Copper complexation and oxygen activation with these ligands are briefly discussed. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00168-3

Tetrahedron: Asymmetry 11 (2000) 2159±2182
Synthesis of N,N-bis[2-(2-pyridyl)ethyl]amino steroids and
related compounds intended as chiral ligands for copper ions
Manuela Gonschior, Manuela Kotteritzsch, Matthias Rost, Bruno Schonecker*
and Ralf Wyrway
Institut fur Organische Chemie und Makromolekulare Chemie der Friedrich-Schiller-Universitat Jena,
È
È
Humboldtstr. 10, D-07743 Jena, Germany
Received 28 March 2000; accepted 3 May 2000
Abstract
Compounds with the N,N-bis[2-(2-pyridyl)ethyl]amino structure (RPY2) are useful tridentate ligands for
copper(I) ions, which can bind and activate oxygen from the atmosphere. For diastereoselective and
enantioselective oxidation reactions, hitherto unknown chiral ligands possessing tripodal structures have
been synthesized starting from homochiral steroids. The double Michael addition of primary steroidal
amines and aminoalcohols to 2-vinyl pyridine was not very succesful. However, homochiral bidentate
ligands with N-[2-(2-pyridyl)ethyl]amino steroid structure could be obtained by this procedure in most
.
cases. New routes (acylation of the bidentate ligands with 2-pyridylacetic acid followed by BH3 THF
reduction, or reductive amination of steroidal ketones, acylation and borane reduction) to the desired tri-
dentate RPY2, also at sterically hindered positions, are described. In the last reaction sequence, `mixed'
tridentate ligands can also be obtained. Copper complexation and oxygen activation with these ligands are
brie¯y discussed. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The reactivity of copper-dioxygen complexes is an interesting ®eld of research1 and is inspired
from the structure of copper-containing monooxygenases such as dopamine b-hydroxylase.2 This
enzyme is characterized by the ability to hydroxylate dopamine at the benzylic position to give
enantioselectively pure (R)-noradrenaline. Studies mimicking these enzymes could show that
copper(I) complexes with tridentate N,N-bis[2-(2-pyridyl)ethyl]amino ligands (Fig. 1) are promising
compounds for binding and activating dioxygen.3
* Corresponding author: Fax: +49-(0)3641-948292; e-mail: c8scbr@uni-jena.de
y
New address: Jenapharm GmbH & Co. KG, Otto-Schott-Str. 15, D-07745 Jena, Germany.
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00168-3

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Figure 1. N,N-Bis-[2-(2-pyridyl)ethyl]amino compounds
As a result of the activation of dioxygen, hydroxylation of the ligand could be observed in most
cases.3a e,g In one case, hydrogen abstraction of exogenous substrates was also described.3f
.
More recently, Reglier and co-workers have employed two suitable prochiral ligands (Fig. 1,
R=2-indanyl,3e cyclopentyl3g) in order to investigate the stereochemistry of the hydroxylation
reaction. For both ligands cis-hydroxylation to yield racemic cis-1-hydroxy-2-amino-indanes3e
and cis-1-hydroxy-2-amino-cyclopentanes3g was observed. In spite of recent advances, homo-
chiral RPY2 ligands, which could open the way to homochiral hydroxylation products, have not
yet been synthesized. We therefore planned the synthesis of such ligands using a homochiral
steroid core with primary amino groups at di€erent positions as starting compounds. In this
paper we describe our results for the Michael addition of primary steroidal amines and vicinal
aminoalcohols to 2-vinyl pyridine which is currently the standard method to obtain RPY2
ligands.3d,g,4 New synthetic routes which are also successful for ligand synthesis at sterically hindered
positions of steroids have been developed. In addition, we discuss some results of copper ion
complexation and dioxygen binding.
The steroid core has the advantage that substituents can be placed at di€erent positions each
having di€erent stereochemical and steric relationships. We chose the d-ring of the 3-methoxy-
estra-1,3,5(10)-triene series for substitution since this ring exhibits a relatively restricted, well-de®ned
conformation5 (Figs. 2 and 3). In particular, we employed derivatives of the four diastereomeric
16-amino-17-hydroxy compounds (1 to 4) for the synthesis of copper complexes5b,6 as well as
for the investigation of the diastereoselective formation of Fe(CO)3 complexes possessing a
planar chirality.7 We then included a series of more ¯exible A-ring-substituted compounds in our
investigations (Figs. 2 and 3). Correspondingly, the four diastereomeric 2-amino-3-hydroxy-
cholestanes (7 to 10) were synthesized from the related azidoalcohols, which we have synthesized
by stereoselective synthesis. Furthermore, we employed 3a- and 3b-amino-cholestanes (compounds
11 and 12 with an axial and equatorial amino group, respectively) as well as the sterically more
hindered 17-amino-3-methoxy-estra-1,3,5(10)-trienes (5 and 6) as model compounds (Fig. 2).
2. Results and discussion
2.1. Synthesis of the steroidal amines and aminoalcohols
The four diastereomeric 16-amino-17-hydroxy-3-methoxy-estra-1,3,5(10)-trienes (1 to 4; Fig. 2)
were synthesized as described in the literature.8 17b-Amino-3-methoxy-estra-1,3,5(10)-triene 5
(Fig. 2) could be obtained in two steps from 3-methoxy-estra-1,3,5(10)-triene-17-one 13 in an
overall yield of 72%. Reduction of the oxime 149 with MoO3/NaBH410a in methanol gave 86% of
the b-amine 510 (Scheme 1). This result is in contrast to a literature report,10a which described the

M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
2161
Figure 2. Primary steroid amines and aminoalcohols
Figure 3. D-Ring and A-ring conformation

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M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
Scheme 1. Synthesis of 17-amines
17a-compound as being the main product.10a Our result was con®rmed by comparing spectral
data of the corresponding 17b-acetamide with the literature results.10 The 17a-amino compound
6 was synthesized, analogously to the androstane and estra-1,3,5(10)-triene series,11 using the
17b-tosylate 16 12 for the azide substitution 17 and the subsequent reduction with LiAlH4 (6, total
yield 57% from 15, Scheme 1).
The synthetic procedure for obtaining the four diastereomeric aminoalcohols 7 to 1013 20 is
outlined in Scheme 2. The azidoalcohols 22, 23, 24 and 26 are intermediates. Compounds 19,21,22
21,23 24,24 10,14 2523 and 2623 were synthesized either as described in the literature or with slight
variations on the literature procedures. The azidoalcohols 22 and 23 could be obtained by either
reduction of the 2a-azido-3-ketone 2123 with lithium borohydride (60% of 2a-azido-3b-ol 22,
33% of 2a-azido-3a-ol 23, 5% of cholestane-3b-ol 18) or with LS-Selectride (82% of 2a-azido-3a-
ol 23, 8% of cholestane-3a-ol). Reduction with sodium borohydride in ethanol gave ca. 50% of
22, 23% of 23 and 15% of cholestane-3b-ol 18. Reduction of the 2b-azido-3-ketone 2523 with
sodium borohydride in ethanol/tetrahydrofuran resulted in the 2b-azido-3b-ol 26 as the only
product. The aminoalcohols were synthesized from the azidoalcohols by reduction with hydrazine
hydrate/Raney-nickel in methanol.14 3a-Amino- and 3b-amino-5a-cholestane (11 and 12) were
synthesized as described in the literature (11 by azide substitution11c of the corresponding 3b-
tosyloxy compound and subsequent reduction with LiAlH4,25,26 12 by reduction of the corre-
sponding 3-oxime with n-amylalcohol/Na27).

M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
2163
Scheme 2. Synthesis of 2,3-aminoalcohols. (a) (i) L-Selectride; (ii) Zn/AcOH/Á; (iii) Mg-monoperphthalate; (b) NaN3/
.
NMP/AcOH/rt; (c) LiBH4; (d) LS-Selectride; (e) NaN3/DMSO/AcOH/Á; (f) N2H4 H2O/Raney-Ni/CH3OH; (g) Jones
ox.; (h) NaBH4
2.2. Addition of steroidal amines and aminoalcohols to 2-vinyl pyridine
The Michael addition of primary amines to 2-vinyl pyridine in re¯uxing methanol and acetic
acid is the standard method for the synthesis of RPY2 ligands. A long reaction time (2 to 5 days)
is necessary. m-Xylylenediamine reacted with 68%,4 n-propylamine with 38%,3g cyclopentylamine
with 40%3g and 2-aminoindane also with 40%.3d The results for the four 16,17-aminoalcohols 1
to 4 using this method with a reaction time of 2 days are given in Scheme 3. Only the sterically less
hindered 16a-amino compounds 1 and 2 resulted in expected RPY2 compounds (31, 32) in low to
moderate yields in addition to the mono(pyridylethyl)amino compounds 27 and 28. The more
hindered 16b-amino compounds formed only the mono(pyridylethyl)amino compounds 29 and 30
in relatively good yields. Variation of the reaction conditions (prolonged reaction times, changing the
ratio of 2-vinyl pyridine and acetic acid) did not improve the yields. Due to the restricted conformation
of the cyclopentane ring5 the 16a-substituent has a quasiequatorial or bisectional character. The
16b-substituent also has a quasiaxial or bisectional conformation. However, in contrast to the
16a-substituents, a sterically unfavourable 1,3-interconversion with the 13b-methyl group exists.
The results for the four 2,3-aminoalcohols 7 to 10 are summarized in Scheme 4. The 2a-amino
compounds (7 and 8) gave the desired RPY2 compounds 37 and 38 only in very low yields. In all
cases the mono(pyridylethyl)amino compounds (33 to 36) could be obtained in moderate yields.
This was an unexpected result since the 2a-substituent is a relatively unhindered equatorial
substituent. The 2b-position has an axial character and a strong 1,3-diaxial steric repulsion with
the 10b-methyl group. A more ¯exible twist-boat conformation (Fig. 3) must be considered,
which is additionaly favoured for compound 10 of the presence of an intramolecular hydrogen
bond in this conformation13 (Fig. 3), (for IR spectra, see Experimental). Nevertheless, a reaction
with two molecules of 2-vinyl pyridine could not be achieved.

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M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
Scheme 3. Hydroamination with 16,17-aminoalcohols
Scheme 4. Hydroamination with 2,3-aminoalcohols

M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
2165
To obtain more insight into this addition reaction and also to obtain chiral RPY2 ligands
without a neighbouring hydroxy group, we investigated the reaction with the axial 3a-amine 11,
the equatorial 3b-amine 12 (Fig. 2) as well as the 17-amines 5 and 6 (17b-5: quasiequatorial, 17a-6:
quasiaxial).
The last two amines are sterically hindered due to the neighbouring ring junction, which is
especially valid for the 17b-amine 5 with a cis arrangement to the 13b-methyl group. It can be seen
from the results in Scheme 5 that the axial 3a-amine only reacted to form the mono(pyridylethyl)-
amine 38, whereas the equatorial 3b-amine reacted to the desired RPY2 compound 40 in addition
to the monadduct 39. As expected, the hindered amine 6 resulted only in the monoadduct 41 and
the most sterically hindered amine 5 did not react at all.
Scheme 5. Hydroamination with 17- and 3-amines
In summary, it is evident that chiral RPY2 ligands with a steroid core generated with low to
moderate yields via addition of primary steroid amines to 2-vinyl pyridine are only available
when sterically relatively unhindered equatorial or quasiequatorial amines (2a, 3b, 16a) are
employed. The corresponding mono(pyridylethyl)amines, however, can generally be synthesized
using this method. In addition, axial steroidal amines can be used as starting materials. Only the
17b-amine 5 cannot be employed due to lack of reactivity. When mixtures of mono- and bis-
addition products are obtained, chromatographic separation is possible. The RPY2 compounds
are in general, less polar than the corresponding monoadducts. The RPY2 steroidal compounds
could not be obtained in crystalline form. Our further investigations were then directed to the
transformation of mono(pyridylethyl)amines to RPY2 ligands. At this point, we should comment
on some very new and important results concerning the bidentate mono(pyridylethyl)amino

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M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
ligands. Itoh, Fukuzumi and co-workers used N-ethyl-N-[2-(2-pyridyl)ethyl]-2-phenethylamine as
a bidentate ligand for Cu(I) ions. The reaction with O2 at ^78ꢀC gave a bis(m-oxo)dicopper(III)
complex. At 25ꢀC the benzylic position of the phenethyl group was hydroxylated.28 Another
bis(m-oxo)dicopper(III) complex with 2-(diethylaminomethyl)-6-phenylpyridine as a bidentate
ligand has the ability to hydroxylate the phenyl ring in ortho-position.29 From these results it is
evident that, except for the tridentate RPY2 ligands, bidentate ligands must be considered as
ligands for copper ions with the ability to bind, activate and transfer oxygen. Therefore, new
routes for the synthesis of N-[2-(2-pyridyl)ethyl]amines are also of interest.
2.3. New routes to N-[2-(2-pyridyl)ethyl]amino and N,N-bis[2-(2-pyridyl)ethyl]amino steroids
Starting with primary amines of steroids, we employed 2-pyridylacetic acid (commercially
available as the hydrochloride) and N,N0-carbonyldimidazole as acylating agents. The amino-
Scheme 6. Synthesis of mono-(pyridylethyl)amines

M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
2167
alcohols 3 and 4 reacted under mild conditions to give the N-pyridylacetamides 42 and 43 in good
yields after an aqueous work-up procedure, which is also suitable for saponi®cation of 17-esters.
Reduction of the amides with borane in THF30 under mild conditions also provided the desired
N-[2-(2-pyridyl)ethyl]amines 29 and 30 in good yields (Scheme 6). Another convenient method is
the reductive amination of steroidal ketones with N-[2-(2-pyridyl)ethyl]amine and NaBH4 in
methanol. In this way we could synthesize from ketone 13 in a one-pot procedure the 17b-N-[2-
(2-pyridyl)ethyl]amino compound 45. Compound 45 is not available by addition of the primary
amine 5 to 2-vinyl pyridine. It is also possible to isolate the imine 44 in high yields (Scheme 6).
For further transformation of the monopyridylethylamino steroids to bispyridylethylamino
steroids we used the acylation/reduction route as previously described. As we could demonstrate
with the sterically hindered monopyridylethylamine 45, the tertiary pyridylacetamide 46 can be
obtained in a smooth reaction. Interestingly enough the 1H NMR spectra of 46 in CDCl3 shows a
Scheme 7. Synthesis of bis-(pyridylethyl)amines

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M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
split signal for the 13b-methyl protons at room temperature. At higher temperatures the expected
singlet appeared. A slow interconversion of the E and Z forms of the tertiary amide 46 at room
temperature is probably responsible for this observation. The reduction of this amide 46 with
borane in THF30 gave the expected 17b-N,N-bis[2-(2-pyridyl)ethyl]amino compound 47 in good
yield. In addition, the 16b-monopyridylethylamine 29 with an additional 17b-hydroxy group
could also be transformed into the 16b-N,N-bis[2-(2-pyridyl)ethyl]amino-17b-hydroxy compound
49. However, the yield is lowerÐespecially for the reduction step (Scheme 7).
Scheme 8. Synthesis of mixed ligands

M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
2169
2.4. Synthesis of tridentate `mixed' ligands
The bidentate monopyridylethylamino ligands described here can be employed in the synthesis
of tridentate mixed ligands. One such mixed ligand containing two di€erent arms at the central
nitrogen is represented by the amide 46; the donor activity of the central nitrogen is strongly
decreased, however, by the amide structure. A second kind of mixed ligand could be obtained by
the Michael addition of 34 to methyl acrylate. Compound 50 represents a tridentate ligand with
N- and O-donor functions (Scheme 8). The reductive amination of ketone 13 with other suitable
amines such as 3-(imidazol-1-yl)propylamine or 3-(N-morpholino)propylamine furnished the
bidentate ligands 51 and 52, respectively. Acylation of 51 with 2-pyridylacetic acid followed by
borane reduction gave the `mixed' tridentate ligand 53 (Scheme 8).
2.5. Synthesis and reactions of copper complexes (preliminary results)
Copper(II) complexes could be obtained by addition of copper(II) perchlorate dissolved in
methanol to a methanolic solution of RPY2 ligands. Reduction of these blue copper(II) complexes
with benzoin/triethylamine3c e,g in either tetrahydrofuran, dichloromethane, or acetonitrile, gave
yellow solutions of copper(I) complexes. Exposure of these solutions to an oxygen atmosphere
caused a colour change to green or blue±green. After 24 h, the isolated copper complexes were
investigated by MS spectroscopy and decomplexed with aq. NH4OH. In the case of the 2a-amino
cholestane compound 38 only the unchanged ligand could been isolated after the described
procedure. In the case of the 16a-amine 32, the mass spectra of the complex as well as the
decomplexed ligand showed, in addition to the molecular ion peaks of the starting material, peaks
of +16 thus indicating the insertion of one oxygen atom. After the described redox procedure with
the 3b-amine 40, only the oxidized ligand could be detected by mass spectroscopy. Further
investigations on this remarkable dependence of oxidation behaviour on the position of the steroid
ligands, including the structure of the oxidation products and the behaviour of bidentate and
mixed ligands, are under way.
3. Conclusions
We have demonstrated that chiral ligands of the type RPY2 with R=steroid core can be syn-
thesized at sterically hindered positions also when new synthetical routes are employed. Further-
more, related bidentate ligands and tridentate `mixed' ligands were described. These ligands are
useful for binding copper ions and dioxygen, thus giving interesting compounds for investigation
on diastereoselective and enantioselective oxidations, in dependence on the structure, the position
and the con®guration of the chiral ligand.
4. Experimental
4.1. General
Melting points were measured on a Boetius micromelting point apparatus (corrected values).
Optical rotations were measured in chloroform with a photoelectronic polarimeter Polamat A

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M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
(Carl Zeiss Jena) at 546 and 578 nm and extrapolated to 589 nm (c in g 100^1 mL^1). IR spectra
were recorded on a Impact 400 spectrometer (NICOLET) in CCl4. UV/vis spectra were obtained
on a Spectrometer Lambda 19 (Perkin±Elmer). Extinction coecients (") are given in l mol^1
cm^1 in parentheses. 1H and 13C NMR spectra were recorded on Bruker spectrometers AC 250 or
DRX 400 in CDCl3 (1H NMR 250 or 400 MHz, 13C NMR 62.5 or 100 MHz). Signals were
assigned by DEPT, COSY±DQF, TOCSY and NOESY. Mass spectra were recorded on an AMD
402 Intectra instrument with electron impact ionization at 70 eV. Elemental analyses were deter-
mined on CHNO-Rapid (HERAEUS) or CHNS-932 (LECO) instruments. MPLC was carried out
using a Labomatic equiqment (MD 80 pump, UV detector). All reactions were monitored by TLC
aluminium sheets, silica gel 60 F254 (Merck), 0.2 mm, detection by UV (254 nm) and spraying
with a solution of conc. sulfuric acid (80 mL), EtOH (20 mL) and vanillin (20 mg) and heating at
170ꢀC. Solvents were puri®ed, dried and distilled according to conventional methods. The reac-
tions were carried out using inert conditions. The steroid compounds 13 and 15 were supplied by
the Schering AG and the Jenapharm GmbH & Co. KG; the other compounds are commercially
available.
4.2. 17ꢀ-Amino-3-methoxy-estra-1,3,5(10)-triene 5
To a solution of 17-hydroximino-3-methoxy-estra-1,3,5(10)-triene9 14 (2.42 g, 8.1 mmol) in abs.
CH3OH (200 mL) and abs. THF (40 mL) MoO3 (2.19 g, 15.2 mmol) were added. After cooling to
0ꢀC NaBH4 (14.8 g, 15.2 mmol) were added in small portions (temperature between 0 and +10ꢀC)
under stirring. The reaction mixture was treated after 30 min at room temperature with KOH (5.0 g)
in H2O (20 mL) and ®ltered o€ after 12 h at 0ꢀC. The residue was washed twice with methanol
(2Â30 mL). The ®ltrate was concentrated in vacuo to 100 mL, poured into ice/water and extracted
with CHCl3 (50 mL). The aqueous phase was extracted twice with CHCl3 (2Â50 mL). The combined
organic phases were washed three times with water (3Â70 mL), dried (Na2SO4) and evaporated.
Yield: 1.7 g (85.8%) of crude 5 as a white powder. M.p. 83±85ꢀC; 1H NMR (CDCl3): ꢁ=0.65 (s,
3H, 18-H3), 2.73 (t, 1H, 17a-H), 2.81 (m, 2H, 6-H2), 3.75 (s, 3H, OCH3), 6.61 (s, 1H, 4-H), 6.69
3
(m, 1H, 2-H), 7.16 (d, J=8.54 Hz; 1H, 1-H); after addition of trichloroacetyl isocyanate (TAI):
3
ꢁ=0.80 (s, 3H, 18-H3), 3.89 (q, 1H, 17a-H), 7.89 (1H, d, J=8.57 Hz, 17b-NHCO), 8.67 (s, 1H,
NH). Puri®cation by recrystallization from ether: m.p. 113±115ꢀC, lit.10b 119±121ꢀC (CH2Cl2±
hexane). N-Acetylation: 70 mg of 5 were dissolved in acetic anhydride (2.0 mL) under re¯ux.
After 30 min at room temperature the acetic anhydride was removed in vacuo and the crystals of
1
the 17b-acetamide10 were dried in vacuum. H NMR (CDCl3): ꢁ=0.70 (s, 3H, 18-H3), 1.98 (s,
3H, CH3CO), 3.97 (m, 1H, 17a-H), 5.31 (d, 3J=8.55 Hz, 1H, 17b-NH).
4.3. 17ꢂ-Amino-3-methoxy-estra-1,3,5(10)-triene 6
The 17b-tosyloxy compound 1612 (5.16 g, 11.7 mmol) and NaN3 (5.68 g, 102.8 mmol) were
reacted at 100ꢀC in abs. HMPTA (70 mL) and 18-crown-6 (1.5 g) for 20 h. After cooling, the
mixture was poured into a ice/water mixture and then extracted with CH2Cl2. The organic phase
was washed several times with water, dried and evaporated in vacuo. Yield: 3.5 g (96.1%) of
17a-azido compound 1711c as an oily product. 1H NMR (CDCl3) ꢁ=0.76 (s, 3H, 18-H3), 3.57 (d,
1H, 17b-H).
Oily 17 (710 mg, 2.28 mmol), dissolved in abs. THF (10 mL), and LiAlH4 (ꢁ1 M in THF,
Fluka, 10 mL) were re¯uxed for 2 h. After cooling (0ꢀC), an ether/H2O mixture was carefully

M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
2171
added. The mixture was treated with a saturated aqueous NH4Cl solution and ®ltered o€. The
residue was washed with ether and the aqueous solution was extracted twice with ether (2Â30
mL). The combined ether solutions were dried and then treated with gaseous HCl. The solid
hydrochloride of 6 was ®ltered o€ and recrystallized from ethanol. Aqueous KOH solution (1 g
KOH, 10 mL H2O), was then slowly added to a concentrated solution of the hydrochloride in
methanol. The mixture was extracted with ether; the ether solution was then washed, dried and
evaporated. Yield: 322 mg (49.5%) of amine 6 as a waxy product. 1H NMR (CDCl3): ꢁ=0.71 (s,
3H, 17b-H), 2.98 (d, 1H, 17b-H); after addition of TAI: ꢁ=0.85 (s, 3H, 18-H3), 3.97 (t, 1H, 17b-H),
3
7.88 (1H, d, J=8.23Hz, 17a-NHCO), 8.73 (s, 1H, NH). N-Acetylation: acetylation of 6 with
acetic anhydride was carried out as described for amine 5; 17a-acetamide:10a m.p. 213±216ꢀC; 1H
NMR (CDCl3): ꢁ=0.82 (s, 3H, 18-H3), 1.98 (s, 3H, CH3CO), 4.04 (t, 1H, 17b-H), 5.35 (d, broad,
1H, 17a-NH).
4.4. 2ꢂ,3ꢂ-Oxido-cholestane 20
To a stirred solution of the bromo ketone 19 (4.7 g, 1.0 mmol) in abs. THF (60 mL) a solution
of L-Selectride (15 mL, 1 M, THF) was added dropwise at ^60ꢀC. After 40 min methanol (15 ml,
1 M, ^40ꢀC) and aqueous H2O2 (30 proz., 10 mL, ^20ꢀC) were added. The mixture was poured
into ice and water/NaCl. After several hours at 10ꢀC the precipitate was ®ltered o€, washed with
water and dried in vacuum. The white solid of 2a-bromo-cholestane-3a-ol22 (4.5 g, 96%, m.p. 98±
105ꢀC) was reduced without further puri®cation by heating with zinc powder (7.5 g, 115 mmol)
and acetic acid (110 mL) with stirring under re¯ux for 30 min. After cooling, the zinc was ®ltered
o€ and washed with acetic acid. The combined acetic acid solutions were poured into water and
extracted with CH2Cl2. The organic phase was washed with aqueous NaHCO3 and water, dried
and evaporated. Puri®cation of the residue by chromatography (SiO2, 0.04±0.06 mm, n-heptane)
gave pure 2-cholestene31 (1.7 g, 48%, m.p. 72±74ꢀC), lit.31 m.p. 74±75ꢀC. A solution of 2-cholestene
(1.7 g, 4.6 mmol) in CH2Cl2 (35 mL) was treated with a solution of magnesium mono-
peroxophthalate hexahydrate (ꢁ85%, 9.7 g, ꢁ16.7 mmol) in methanol (35 mL) under stirring at
room temperature. After 6 h an aqueous sodium hydrosul®te solution was added. After addition
of CH2Cl2 the organic phase was separated, the aqueous phase was extracted with CH2Cl2 and
the combined organic solutions were washed with water, dried and evaporated in vacuum. The
oily residue was crystallized with methanol giving a-epoxide 20 (1.5 g, 84%, m.p. 100±102ꢀC);
lit.31 m.p. 105±106ꢀC.
4.5. 2ꢀ-Azido-cholestane-3ꢂ-ol 24 24
A mixture of a-epoxide 20 (3.0 g, 7.8 mmol), abs. dimethyl sulfoxide (60 mL), acetic acid (12
mL) and sodium azide (3.6 g, 55.4 mmol) was heated at 110ꢀC under stirring for 4 h. CAUTION!
Hydrazoic acid is explosive and poisonous. After cooling, the mixture was poured into ice and
water/NaCl. The precipitation was ®ltered o€, washed with water and dried in vacuum giving 3.2
g of azidoalcohol 24 (95%, m.p. 128±138ꢀC), crystallization with methanol gave 2.7 g of 24 (81%,
m.p. 139±142ꢀC), lit.24 m.p. 142ꢀC; [ꢂ]D20=+45 (c=0.57, CHCl3), lit.24 ‰ꢂŠD20=+40 (c=1.0,
1
CHCl3); H NMR (CDCl3): ꢁ=0.62 (s, 3H, 18-H3), 0.95 (s, 3H, 19-H3), 3.75 (m, 1H, 2a-H),
3.82 (m, 1H, 3b-H); after addition of TAI: 3.93 (m, 1H, 2a-H), 4.89 (m, 1H, 3b-H), 8.32 (s, 1H,
NH).

2172
M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
4.6. 2ꢀ-Amino-cholestane-3ꢂ-ol14 10
To a solution of azidoalcohol 24 (1.0 g, 2.3 mmol) in methanol (30 mL) and THF (5 mL) 80%
hydrazine hydrate (2 mL) and a small portion of Raney-nickel were added. After 15 min heating
under re¯ux and stirring the Raney-nickel was ®ltered o€ and washed with hot dichloromethane.
The solution was concentrated in vacuum for crystallization and after cooling the crystals were
®ltered o€ and washed with cold methanol giving 776 mg of 24 (84%); m.p. 180±186ꢀC, lit.14 m.p.
206±207ꢀC, lit.13 m.p. 184±187ꢀC,{ lit.15 m.p. 177±179ꢀC; ‰ꢂŠD20=+29 (c=0.50, CHCl3), lit.14+34
(pyridine), lit.15+46.5 (ethanol); IR (CCl4), ꢃ [cm^1]: 3627 (ms), 3329 (br, ms); 1H NMR (CDCl3):
ꢁ=0.62 (s, 3H, 18-H3), 0.97 (s, 3H, 19-H3), 3.00 (m, 1H, 2a-H), 3.66 (m, 1H, 3b-H); after addition
of TAI: ꢁ=4.16 (m, 1H, 2a-H), 5.07 (m, 1H, 3b-H) 8.25 (d, 1H, 2b-NHCO), 8.42 and 8.81 (2Âs,
2Â1H, 2ÂNH). C27H49NO HRMS m/z (M+): 403.3828; calcd: 403.3812.
4.7. Reduction of 2ꢂ-azido-cholestane-3-one23 21 with LiBH4
To a solution of azido ketone 21 (1.0 g, 2.3 mmol) in methanol (30 mL) and THF (30 mL)
lithium borohydride (0.4 g, 18.3 mmol) was successively added under stirring at 0ꢀC. After 30 min
acetone (10 mL) was added and the solution was poured into an ice/water mixture. The pre-
cipitate was ®ltered o€ after cooling for several hours, washed with water and dried in vacuum
giving 0.98 g of a white powder.
Chromatography on silica gel (0.04±0.06 mm) with toluene gave 2a-azido-cholestane-3a-ol 23
(0.33 g, 33%), 2a-azido-cholestane-3b-ol 22 (0.60 g, 59%) and cholestane-3b-ol 18 (45 mg, 5%).
20
Compound 23: m.p. 105±109ꢀC (methanol); ‰ꢂŠD =^23 (c=0.50, CHCl3); H NMR (CDCl3):
ꢁ=0.63 (s, 3H, 18-H3), 0.80 (s, 3H, 19-H3), 3.53 (m, 1H, 2b-H), 3.95 (m, 1H, 3b-H); after addition of
TAI: 3.42 (m, 1H, 2b-H), 5.25 (m, 1H, 3b-H), 8.36 (s, 1H, NH). C27H47N3O (429.26) calcd: C, 75.54;
H, 10.95; N, 9.78; found: C, 75.15; H, 11.24; N, 9.56. HRMS m/z (M+): 429.3725; calcd: 429.3717.
1
20
Compound 22: m.p. 103±105ꢀC (methanol); ‰ꢂŠD =^42 (c=0.50, CHCl3); H NMR (CDCl3):
ꢁ=0.63 (s, 1H, 18-H3), 0.83 (s, 3H, 19-H3), 3.29±3.47(m, 2H, 2b-H, 3a-H); after addition of TAI:
3.57 (m, 1H, 2b-H), 4.71 (m, 1H, 3a-H), 8.34 (s, 1H, NH). C27H47N3O (429.26) calcd: C, 75.54;
H, 10.95; N, 9.78; found: C, 74.92; H, 10.98; N, 9.32. HRMS m/z (M+): 429.3724; calcd: 429.3717.
1
4.8. Reduction of 21 with LS-Selectride
To a solution of 21 (1.0 g, 2.3 mmol) in THF (40 mL) a solution of LS-Selectride in THF (1 M, 10
mL) was added at ^60ꢀC under stirring. After 40 min methanol (10 mL, ^50ꢀC), sodium hydroxide
in methanol (1 M, 10 mL, ^30ꢀC) and 30% H2O2 (5 mL, ^10ꢀC) were added. The mixture was
successively added to ice and water/NaCl under stirring. After cooling for several hours the pre-
cipitate was ®ltered o€, washed with water, dried in vacuum and puri®ed by chromatography on
silica gel (0.04^0.06 mm) with toluene to give 23 (0.82 g, 82%) and cholestane-3a-ol32 (80 mg, 8%).
4.9. 2ꢀ-Azido-cholestane-3ꢀ-ol 26
To a stirred suspension of azido ketone 25 (300 mg, 0.7 mmol) in ethanol (2 mL) NaBH4 (90
mg, 2.4 mmol) was added at 0ꢀC. After 30 min at room temperature ice and water were added.
{
Lit.13: see discussion on m.p. and IR spectra.

M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
2173
The precipitate was ®ltered o€ after cooling for several hours, washed with water and dried in
vacuum giving 2b,3b-azidoalcohol 26 (269 mg, 89%, m.p. 138±144ꢀC). Crystallization with
methanol/ethyl acetate gave white crystals. M.p. 143±147ꢀC; ‰ꢂŠD20=+58 (c=1.0, CHCl3); 1H NMR
(CDCl3): ꢁ=0.63 (s, 3H, 18-H3), 0.98 (s, 3H, 19-H3), 3.59 (m, 1H, 3a-H), 3.99 (m, 1H, 2a-H);
after addition of TAI: 4.15 (m, 1H, 2a-H), 4.88 (m, 1H, 3a-H), 8.42 (s, 1H, NH). C27H47N3O
(429.26) calcd: C, 75.54; H, 10.95; N, 9.78; found: C, 75.12; H, 11.04; N, 9.37.
4.10. 2ꢂ-Amino-cholestane-3ꢀ-ol 8
A solution of azidoalcohol 22 (1.74 g, 4.0 mmol) in methanol (50 mL) and THF (10 mL) was
reacted with 80% hydrazine hydrate (2.5 mL) and Raney-nickel as described for the synthesis of
10. Crystallization with ethyl acetate and methanol gave 8 as white crystals (1.25 g, 77%, m.p.
158±165ꢀC), lit.17 m.p. 162±164ꢀC, lit.18 m.p. 260±265ꢀC;x ‰ꢂŠD20=+7 (c=0.9, CHCl3), lit.17
‰ꢂŠ2D0=+7 (c=1.06, CHCl3); IR (CCl4), ꢃ [cm^1]: 3329 (vbr, s); 1H NMR (CDCl3): ꢁ=0.62 (s, 3H,
18-H3), 0.81 (s, 3H, 19-H3), 2.58 (m, 1H, 2b-H), 3.10 (m, 1H, 3a-H); after addition of TAI: 4.11
(m, 1H, 2b-H), 4.75 (m, 1H, 3a-H), 7.87 (d, 1H, 2a-NHCO), 8.37 and 8.39 (2Âs, 2Â1H, 2ÂNH).
C27H49NO HRMS m/z (M+): 403.3834; calcd: 403.3812.
4.11. 2ꢂ-Amino-cholestane-3ꢂ-ol 7
A solution of azidoalcohol 23 (1.28 g, 3.0 mmol) in methanol (40 mL) and THF (10 mL) was
reacted with 80% hydrazine hydrate (2.3 mL) and Raney-nickel as described for the synthesis of
10. Crystallization with ethyl acetate/methanol gave 7 as white crystals (1.02 g, 84%, m.p. 205±
208ꢀC), lit.18 m.p. 225±226ꢀC (ethanol).{ ‰ꢂŠD20=+44 (c=0.64, CHCl3); IR (CCl4), ꢃ [cm^1]: 3480
1
(br, ms), 3329 (br, ms); H NMR (CDCl3), ꢁ=0.62 (s, 3H, 18-H3), 0.77 (s, 3H, 19-H3), 2.97 (m,
1H, 2b-H), 3.68 (m, 1H, 3b-H); after addition of TAI: 4.17 (m, 1H, 2b-H), 5.23 (m, 1H, 3b-H),
7.91 (d, 1H, 2b-NHCO), 8.39 and 8.44 (2Âs, 2Â1H, 2ÂNH). C27H49NO (403.70) calcd: C, 80.33;
H, 12.23; N, 3.47; found: C, 79.93; H, 12.23; N, 3.43; HRMS m/z (M+): 403.3829; calcd: 403.3812.
4.12. 2ꢀ-Amino-cholestane-3ꢀ-ol 9
A solution of azidoalcohol 26 (300 mg, 0.70 mmol) in methanol (20 mL) was reacted with 80%
hydrazine hydrate (1 mL) and Raney-nickel as described for the synthesis of 10 giving after
crystallization with ethyl acetate/methanol amiꢀnoalcohol 9 (240 mg, 85%, m.p. 155±160ꢀC and
209±211ꢀC), lit.19 m.p. 166±169ꢀC or 148±149 C,k respectively, lit.20 m.p. 209±211ꢀC (EtOH);
‰ꢂŠ2D0=+41 (c=0.50, CHCl3), lit.20 ‰ꢂŠ2D0=+10 (c=1.0, CHCl3); IR (CCl4), ꢃ (cm^1): 3460 (w), 3217
(br, ms); 1H NMR (CDCl3): ꢁ=0.62 (s, 3H, 18-H3), 0.95 (s, 3H, 19-H3), 3.13 (m, 1H, 2a-H), 3.51
(m, 1H, 3a-H); after addition of TAI: 4.53 (m, 1H, 2a-H), 4.99 (m, 1H, 3a-H), 8.24 (d, 1H,
.
2aNHCO), 8.28 and 8.67 (2Âs, 2Â1H, 2ÂNH). C27H49NO 1/2H2O (412.70) calcd: C, 78.58; H,
12.21; N, 3.39; found: C, 78.08; H, 11.99; N, 3.23. HRMS m/z (M+): 403.3807; calcd: 403.3812.
x
{
k
Lit.13: see discussion on m.p. and IR spectra.
Lit.13: see discussion on m.p. and IR spectra.
Lit.13: see discussion on m.p. and IR spectra.

2174
M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
4.13. General method for the addition of primary amino steroids to 2-vinyl pyridine
4.13.1. Addition of aminoalcohol 1
Aminoalcohol 1 (500 mg, 1.66 mmol) was dissolved at room temperature in a solution of abs.
CH3OH (10 mL) and 2-vinyl pyridine (10 mL, 9.76 g, 92.8 mmol, puri®ed by passing through a
short column with silica gel and ether as solvent, followed by removal of the solvent). After
addition of acetic acid (600 mg, 10 mmol), the mixture was stirred for 48 h at 75ꢀC under argon
and in the absence of light. The solvents were removed under reduced pressure and the resulting
oil was dissolved in CH3OH (10 mL). Methanolic NaOH (1 M, 5 mL) was added, the solvent was
removed and the residue extracted with ether or CH2Cl2. After evaporation of the solvent, the
reaction mixture was separated with column chromatography on silica gel (50 g) using CH3OH
as solvent or by MPLC on silica gel with ethyl acetate:CH3OH (7:3) for the chloestane
compounds.
Fraction 1: 16a-N,N-Bis-[2-(2-pyridyl)ethyl]amino-3-methoxy-estra-1,3,5(10)-triene-17a-ol 31,
178 mg (21%), colourless oil; ‰ꢂŠ2D0=+40 (c=0.5, CHCl3); 1H NMR (CDCl3): ꢁ=0.72 (s, 3H, 18-H3),
3
2.75±3.42 (m, 11H, 6-H2, 2ÂCH2CH2Py, 16b-H), 3.62 (d, J=4.1 Hz, 1H, 17b-H), 3.75 (s, 3H,
3
OCH3), 6.59 (s, 1H, 4-H), 6.69 (d, J=8.60 Hz, 1H, 2-H), 7.05±7.19 (m, 5H, 1-H, 2Â3-Hpy and
5-Hpy), 7.56 (t, 3J=7.6 Hz, 2H, 2Â4-Hpy), 8.52 (d, 3J=5.8 Hz, 2H, 2Â2-Hpy); 13C NMR (CDCl3):
ꢁ=17.15 (18-C), 25.10, 28.07, 29.86, 31.35, 35.52, 38.83, 43.50, 45.02, 46.91, 51.26, 55.19 (OCH3),
64.52 (16-C), 78.32 (17-C), 111.40 (Car), 113.80 (Car), 121.21 (Cpy), 123.35 (Cpy), 126.26 (Car),
132.98 (Car), 136.32 (Cpy), 137.90 (Car), 149.32 (Cpy), 157.39 (Car),160.09 (Cpy). C33H41N3O2
(511.72) calcd: C, 77.46; H, 8.07; N, 8.41; found: C, 76.68; H, 8.14; N, 8.26.
Fraction 2: 16a-N-[2-(2-Pyridyl)ethyl]amino-3-methoxy-estra-1,3,5(10)-trien-17a-ol 27, 380 mg
20
1
(56%), colourless oil; ‰ꢂŠD =+25 (c=0.50, CHCl3); H NMR (CDCl3): ꢁ=0.71 (s, 3H, 18-H3),
2.75±3.12 (m, 6H, 6-H2, CH2CH2Py), 3.33 (m, 1H, 16b-H), 3.56 (d, 3J=4.75 Hz, 1H, 17b-H), 3.75
(s, 3H, OCH3), 6.59 (s, 1H, 4-H), 6.68 (d, J=8.53 Hz, 1H, 2-H), 7.09±7.18 (m, 3H. 1-H, 3-Hpy
and 5-Hpy), 7.61 (m, 1H, 4-Hpy), 8.52 (d, J=4.0 Hz, 1H, 2-Hpy); 13C NMR (CDCl3): ꢁ=16.85
3
3
(18-C), 25.88, 28.06, 29.87, 31.80, 33.72, 37.97, 38.80, 43.51, 45.84, 46.29, 47.91, 55.18 (OCH3),
59.78 (16-C), 76.36 (17-C), 111.40 (Car), 113.80 (Car), 121.41 (Cpy), 123.35 (Cpy), 126.31 (Car),
132.93 (Car), 136.51 (Cpy), 137.89, (Car), 149.27 (Cpy), 157.38 (Car), 159.85 (Cpy). C26H34N2O2
(406.57) calcd: C, 76.81; H, 8.43; N, 6.89; found: C, 76.19; H, 8.40; N, 6.88.
4.13.2. Addition of aminoalcohol 2
Aminoalcohol 2 (500 mg, 1.66 mmol) were reacted with 2-vinyl pyridine as described for the
reaction of aminoalcohol 1.
Fraction 1: 16a-N,N-Bis-[2-(2-pyridyl)ethyl]amino-3-methoxy-estra-1,3,5(10)-triene-17b-ol 32,
350 mg (41%), colourless oil; ‰ꢂŠ2D0=+4 (c=0.4, pyridine); 1H NMR (CDCl3): ꢁ=0.82 (s, 3H, 18-H3),
2.75±2.96 (m, 10H, 6-H2, 2ÂCH2CH2Py), 3.29 (m, 2H, 16b-H, 17a-H), 3.75 (s, 3H, OCH3), 6.60
(s, 1H, 4-H), 6.68 (d, 3J=8.52 Hz, 1H, 2-H), 6.93±7.19 (m, 5H, 1-H, 2Â3-Hpy and 5-Hpy), 7.53 (t,
3
3J=7.1 Hz, 2H, 2Â4-Hpy), 8.49 (d, J=4.8 Hz, 2H, 2Â2-Hpy); 13C NMR (CDCl3): ꢁ=12.28
(18-C), 25.32, 26.07, 27.25, 29.76, 36.20, 37.00, 38.51, 42.41, 43.86, 48.89, 51.44, 55.16 (OCH3),
66.20 (16-C), 83.81 (17-C), 111.38 (Car), 113.79 (Car), 121.08 (Cpy), 123.48 (Cpy), 126.21 (Car),
132.79 (Car), 136.27 (Cpy), 137.91 (Car), 149.00 (Cpy), 157.40 (Car), 160.68 (Cpy). C33H41N3O2
(511.72) calcd: C, 77.46; H, 8.07; N, 8.41; found: C, 77.19; H, 8.23; N, 6.01.
Fraction 2: 16a-N-[2-(2-Pyridyl)ethyl]amino-3-methoxy-estra-1,3,5(10)-triene-17b-ol 28, 203
mg (30%), colourless oil; ‰ꢂŠ2D0=+30 (c=0.50, CHCl3); 1H NMR (CDCl3): ꢁ=0.81 (s, 3H, 18-H3),

M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
2175
3
2.76±3.14 (m, 7H, 6-H2, 16b-H, CH2CH2Py), 3.48 (d, J=6.5 Hz, 1H, 17a-H), 3.75 (s, 3H,
OCH3), 6.59 (s, 1H, 4-H), 6.68 (q, 1H, 2-H), 7.10±7.19 (m, 3H, 1-H, 3-Hpy and 5-Hpy), 7.60 (m,
1H, 4-Hpy), 8.50 (m, 1H, 2-Hpy); 13C NMR (CDCl3): ꢁ=12.26 (18-C), 26.04, 27.16, 29.74, 31.65,
36.82, 37.87, 38.44, 43.73 (2 C, overlapped), 43.91, 48.06, 55.17 (OCH3), 63.90 (16-C), 87.94
(17-C), 111.43 (Car), 113.80 (Car), 121.33 (Cpy), 123.39 (Cpy), 126.20 (Car), 132.57 (Car), 136.56
(Cpy), 137.90 (Car), 149.16 (Cpy), 157.42 (Car), 160.16 (Cpy). C26H34N2O2 (406.57) calcd: C, 76.81;
H, 8.43; N, 6.89; found: C, 76.50; H, 8.25; N, 6.79.
4.13.3. Addition of aminoalcohol 3
Aminoalcohol 3 (400 mg, 1.33 mmol) was reacted with 2-vinyl pyridine as described for the
reaction of aminoalcohol 1.
16b-N-[2-(2-Pyridyl)ethyl]amino-3-methoxy-estra-1,3,5(10)-triene-17b-ol 29: 406 mg (75%),
1
colourless oil; H NMR (CDCl3): ꢁ=0.62 (s, 3H, 18-H3), 2.81 (m, 2H, 6-H2), 2.92±3.15 (m, 5H,
CH2CH2Py, 16a-H), 3.37 (d, 3J=8.8 Hz, 1H, 17a-H), 3.75 (s, 3H, OCH3), 6.60 (s, 1H, 4-H), 6.68
(q, 1H, 2-H), 7.09±7.20 (m, 3H, 1-H, 3-Hpy and 5- Hpy), 7.59 (m, 1H, 4-Hpy), 8.51 (m, 1H, 2-Hpy);
13C NMR (CDCl3): ꢁ=12.30 (18-C), 26.23, 27.58, 29.74, 35.16, 37.64, 38.17, 38.63, 43.29, 43.95,
47.18, 49.66, 55.16 (OCH3), 58.05 (16-C), 79.06 (17-C), 111.42 (Car), 113.78 (Car), 121.30 (Cpy),
123.28 (Cpy), 126.30 (Car), 132.69 (Car), 136.37 (Cpy), 137.76 (Car), 149.29 (Cpy), 157.43 (Car), 160.00
(Cpy); C26H34N2O2 (406.57) calcd: C, 76.81; H, 8.43; N, 6.89; found: C, 77.09; H, 8.73; N, 6.71.
4.13.4. Addition of aminoalcohol 4
Aminoalcohol 4 (980 mg, 3.25 mmol) was reacted with 2-vinyl pyridine as described for the
reaction of aminoalcohol 1.
16b-N-[2-(2-Pyridyl)ethyl]amino-3-methoxy-estra-1,3,5(10)-triene-17a-ol 30: 610 mg (46%),
1
colourless oil; H NMR (CDCl3): ꢁ=0.81 (s, 3 H, 18-H3), 2.81 (m, 2H, 6-H2), 2.95±3.11 (m, 5H,
16a-H, CH2CH2Py), 3.60 (s, 1 H, 17b-H), 3.75 (s, 3 H, OCH3), 6.61-6.71 (m, 2 H, 4-H, 2-H),
7.04-7.21 (m, 3 H,1-H, 3-Hpy and 5-Hpy), 7.57 (m, 1 H, 4-Hpy), 8.49 (m, 1 H, 2-Hpy); 13C NMR
(CDCl3): ꢁ=17.82 (18-C), 25.89, 27.94, 29.81, 32.02, 33.51, 37.69, 38.62, 43.35, 44.27, 47.87,
48.03, 55.19 (OCH3), 68.50 (16-C), 84.63 (17-C), 111.46 (Car), 113.79 (Car), 121.34 (Cpy), 123.37
(Cpy), 126.25 (Car), 132.65 (Car), 136.47 (Cpy), 137.92 (Car), 149.14 (Cpy), 157.45 (Car), 160.28
(Cpy). C26H34N2O2 (406.57) calcd: C, 76.81; H, 8.43; N, 6.89; found: C, 76.74; H, 8.62; N, 6.73.
4.13.5. Addition of 17ꢂ-amine 6
Compound 6 (400 mg, 1.40 mmol) was reacted with 2-vinyl pyridine as described for the reac-
tion of aminoalcohol 1.
17a-N-[2-(2-Pyridyl)ethyl]amino-3-methoxy-estra-1,3,5(10)-triene 41: 140 mg (25%), colourless
oil; ‰ꢂŠ2D0=+32.9 (c=0.24, CHCl3); 1H NMR (CDCl3): ꢁ=0.71 (s, 3H, 18-H3), 2.67 (d, 1H, 17b-H),
2.82 (m, 2H, 6-H2), 2.90±3.02 (m, 4H, CH2CH2Py), 3.75 (s, 3H, OCH3), 6.60 (s, 1H, 4-H), 6.68 (q,
1H, 2-H), 7.07±7.18 (m, 3H, 1-H, 3-Hpy and 5-Hpy), 7.56 (t, 4-Hpy), 8.52 (m, 1H, 2-Hpy).
4.13.6. Addition of aminoalcohol 7
Aminoalcohol 7 (800 mg, 1.98 mmol) was reacted with 2-vinyl pyridine as described for the
reaction of the aminoalcohol 1.
Fraction 1: 2a-N,N-Bis-[2-(2-pyridyl)ethyl]amino-5a-cholestane-3a-ol 37, 97 mg (8%), colour-
less oil; ‰ꢂŠ2D0=+13 (c=0.88, CH3OH). UV (CH3OH): lmax (lg ")=261 nm (3.6904). H NMR
1
(CDCl3): ꢁ=0.63 (s, 3H, 18-H3), 0.74 (s, 3H, 19-H3), 0.84 (s, 6H, 26-H3 and 27-H3), 0.87 (d,

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M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
3J=6.6 Hz, 3H, 21-H3), 2.55 (m, 1H, 2b-H), 2.81±2.93 (m, 6H, CH2CH2Py), 3.18 (m, 2H,
CH2CH2Py), 3.81 (m, 1H, 3b-H), 6.98±7.06 (m, 4H, 2Â3-Hpy and 5-Hpy), 7.48 (t, 3J=7.6 Hz, 2H,
3
2Â4-Hpy), 8.47 (d, 2H, J=4.2 Hz, 2Â2-Hpy); 13C NMR (CDCl3): ꢁ=12.0 (18-C), 12.4 (19-C),
18.6 (21-C), 20.8 (11-C), 22.5 and 22.7 (26-C and 27-C), 23.7 and 24.1 (23-C and 15-C), 27.9 (25-C),
28.1 (6-C), 31.8 (16-C), 34.5 (4-C), 35.0 (7-C and 20-C), 35.7 (8-C and 2ÂCH2CH2Py), 36.1 (22-C),
36.4 (10-C), 38.4 (5-C), 39.4 (24-C and 12-C), 40.0 (1-C), 42.4 (13-C), 49.1 (2ÂCH2CH2Py), 54.4
(9-C), 56.0 and 56.3 (14-C and 17-C), 58.6 (2-C), 67.8 (3-C), 120.9 (2Â3-or 5-Cpy), 123.6 (2Â3-or
5-Cpy), 136.1 (2Â4-Cpy), 148.9 (2Â2-Cpy), 160.4 (2Â6-Cpy). HRMS m/z 595.4864 (M+^H2O),
calcd: 595.4879 for C41H61N3.
Fraction 2: 2a-N-[2-(2-Pyridyl)ethyl]amino-5a-cholestane-3a-ol 33, 482 mg (48%), white solid.
M.p. 73±77ꢀC (CH3OH); ‰ꢂŠ2D0=+33 (c=1.03, CH3OH). UV (CH3OH): lmax (lg ")=260 nm
(3.5442). 1H NMR (CDCl3): ꢁ=0.60 (s, 3H, 18-H3), 0.76 (s, 3H, 19-H3), 0.83 (d, 6H, 26- and 27-H3),
0.86 (d, 3H, 21-H3), 2.64 (m, 1H, 2b-H), 2.93±3.11 (m, 4H, CH2CH2Py), 3.92 (m, 1H, 3b-H), 7.13
3
3
(m, 2H, 3- and 5-Hpy), 7.58 (t, 1H, J=7.6 Hz, 4-Hpy), 8.50 (d, J=4.1 Hz, 2-Hpy); 13C NMR
(CDCl3): ꢁ=11.9 (18-C), 12.4 (19-C), 18.6 (21-C), 20.7 (11-C), 22.5 and 22.7 (26-C and 27-C),
23.7 and 24. 1 (23-C and 15-C), 27.8 (16-C), 27.9 (25-C), 28.1 (6-C), 31.8 (7-C), 33.3 (4-C), 35.0
(20-C), 35.7 and 36.0 (8-C and 22-C), 36.3 (10-C), 38.1 (CH2CH2Py), 38.3 (5-C), 39.4 and 39.8
(24-C and 12-C), 39.9 (1-C), 42.4 (13-C), 45.1 (CH2CH2Py), 54.1 (9-C), 55.4 (2-C), 56.1 and 56.3
(14-C and 17-C), 64.6 (3-C), 121.3 (3-or 5-Cpy), 123.4 (3-or 5-Cpy), 136.4 (4-Cpy), 149.1 (2-Cpy),
159.9 (6-Cpy). HRMS m/z 490.4279 (M+^H2O), calcd: 490.4284 for C34H54N2.
4.13.7. Addition of aminoalcohol 8
Aminoalcohol 8 (800 mg, 1.98 mmol) was reacted with 2-vinyl pyridine as described for the
reaction of aminoalcohol 1.
Fraction 1: 2a-N,N-Bis-[2-(2-pyridyl)ethyl]amino-5a-cholestane-3b-ol 38, 134 mg (11%), colour-
less oil; ‰ꢂŠ2D0=+31 (c=0.83, CH3OH). UV (CH3OH): lmax (lg ")=261 (3.8784) and 285 (1.9347);
1H NMR (CDCl3): ꢁ=0.62 (s, 3H, 18-H3), 0.79 (s, 3H, 19-H3), 0.83 (d, 6H, 26-H3 and 27-H3),
3
0.85 (d, 3H, J=6.5 Hz, 21-H3), 2.55 (t, 1H, 2b-H), 2.72±3.07 (m, 8H, 2ÂCH2CH2Py), 3.23 (t,
1H, 3b-H), 6.93 and 7.07 (d and m, 2Â2H, 2Â3-Hpy and 2Â5-Hpy), 7.50 (t, 2H, 2Â4-Hpy), 8.50 (d,
3J=3.9 Hz, 2H, 2Â2-Hpy). HRMS m/z 595.4872 (M+-H2O), calcd: 595.4879 for C41H61N3.
Fraction 2: 2a-N-[2-(2-Pyridyl)ethyl]amino-5a-cholestane-3b-ol 34, 543 mg (54%), white solid.
M.p. 126±129ꢀC (CH3OH); ‰ꢂŠD20=+22 (c=0.68, pyridine). UV (CH3OH): lmax (lg ")=260 nm
1
(3.4867); H NMR (CDCl3): ꢁ=0.62 (s, 3H, 18-H3), 0.79 (s, 3H, 19-H3), 0.83 (d, 6H, 26-H3 and
3
27-H3), 0.87 (d, 3H, J=6.5 Hz, 21-H3), 2.39 (m, 3H, CH2CH2Py), 2.43 (t, 1H, 2b-H), 3.19 (m,
2H, 3a-H and CH2CH2Py), 7.11 (m, 2H, 3-Hpy and 5-Hpy), 7.58 (t, 3J=7.7 Hz, 4J=1.8 Hz, 1H, 4-Hpy),
8.50 (d, 3J=4.0 Hz, 1H, 2-Hpy). HRMS m/z 507.4299 (M+^1), calcd: 507.4311 for C34H55N2O.
4.13.8. Addition of aminoalcohol 9
Aminoalcohol 9 (800 mg, 1.98 mmol) was reacted with 2-vinyl pyridine as described for the
reaction of aminoalcohol 1.
2b-N-[2-(2-Pyridyl)ethyl]amino-5a-cholestane-3b-ol 35: 483 mg (48%), white solid. M.p. 137±
141ꢀC (CH3OH); ‰ꢂŠ2D0=+32 (c=0.68, CHCl3); 1H NMR (CDCl3): ꢁ=0.60 (s, 3H, 18-H3), 0.70 (s,
3
3H, 19-H3), 0.83 (d, 6H, 26-H3 and 27-H3), 0.87 (d, 3H, J=6.5 Hz, 21-H3), 2.84 (m, 2H, 2a-H
and CH2CH2Py), 2.94±3.26 (m, 3H, CH2CH2Py), 3.48 (m, 1H, 3a-H), 7.14 (m, 2H, 3-Hpy and 5-Hpy),
7.58 (t, 1H, 3J=6.8 Hz, 4J=1.7 Hz, 4-Hpy), 8.50 (d, 1H, 3J=4.0 Hz, 2-Hpy). HRMS m/z 490.4270
(M+^H2O), calcd: 490.4284 for C34H54N2.

M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
2177
4.13.9. Addition of aminoalcohol 10
Aminoalcohol 10 (800 mg, 1.98 mmol) was added to 2-vinyl pyridine as described for the
reaction of aminoalcohol 1.
2b-N-[2-(2-Pyridyl)ethyl]amino-5a-cholestane-3a-ol 36: 402 mg (40%), white solid. M.p. 101±
20
105ꢀC (CH3OH); ‰ꢂŠD =+35 (c=0.68, CHCl3); H NMR (CDCl3): ꢁ=0.61 (s, 3H, 18-H3), 0.84
(d, 6H, 26-H3 and 27-H3), 0.86 (s, 3H, 19-H3), 0.89 (d, 3H, 3J=6.4 Hz, 21-H3), 2.73 (d, 1H, 3J=5.2
Hz, 2a-H), 2.93±3.01 (m, 4H, CH2CH2Py), 3.75 (m, 1H, 3b-H), 7.12 (d and t, 2H, 3-Hpy and
1
3
3
5-Hpy), 7.57 (t, J=7.7 Hz, 1H, 4-Hpy), 8.50 (d, J=4.0 Hz, 1H, 2-Hpy). HRMS m/z 507.4316
(M+^1), calcd: 507.4311 for C34H55N2O.
4.13.10. Addition of 3ꢂ-amine 11
Compound 11 (718 mg, 1.85 mmol) was reacted with 2-vinyl pyridine as described for the
reaction of the aminoalcohol 1.
3a-N-[2-(2-Pyridyl)ethyl]amino-5a-cholestane 38: 477 mg (52%), white solid. M.p. 115±117ꢀC;
‰ꢂŠ2D0=+19 (c=0.61, CHCl3); 1H NMR (CDCl3): ꢁ=0.63 (s, 3H, 18-H3), 3.19±3.23 (m, 5H, 3b-H,
3
CH2CH2Py), 7.15±7.19 (m, 2H, 3-Hpy and 5-Hpy), 7.61 (m, 1H, 4-Hpy), 8.44 (d, J=5.6 Hz, 1H,
2-Hpy). Bis-picrate (yellow crystals): C46H62N8O14 (951.04) calcd: C, 58.09; H, 6.57; N, 11.78;
found: C, 57.55; H, 6.78; N, 11.54
4.13.11. Addition of 3ꢀ-amine 12
Compound 12 (360 mg, 0.93 mmol) was reacted with 2-vinyl pyridine as described for the
reaction of aminoalcohol 1.
Fraction 1: 3b-N,N-Bis-[2-(2-pyridyl)ethyl]amino-5a-cholestane 40, 110 mg (20%), colourless oil;
‰ꢂŠ2D0=+15 (c=0.94, CHCl3); 1H NMR (CDCl3): ꢁ=0.61 (s, 3H, 18-H3), 0.82 (s, 3H, 19-H3), 0.86
(d, 6H, 26- and 27-H3), 0.90 (d, 3H, 21-H3), 2.56 (m, 1H, 3a-H), 2.89 (m, 6H, 2ÂCH2CH2Py), 7.06
(m, 4H, 2Â3-Hpy and 5-Hpy), 7.53 (m, 2H, 2Â4-Hpy), 8.48 (m, 2H, 2-Hpy). Tris-picrate (yellow crystals):
C59H72N12O21 (1285.29) calcd: C, 55.13; H, 5.65; N, 13.08; found: C, 54.72; H, 5.83; N, 12.44.
Fraction 2: 3b-N-Bis-[2-(2-pyridyl)ethyl]amino-5a-cholestane 39: 200 mg (44%), colourless oil;
20
1
‰ꢂŠD =+20 (c=0.96, CHCl3); H NMR (CDCl3): ꢁ=0.61 (s, 3H, 18-H3), 2.46 (m, 1H, 3a-H),
2.94±3.03 (m, 4H, CH2CH2Py), 7.07±7.16 (m, 2H, 3-Hpy and 5-Hpy), 7.56 (m, 1H, 4-Hpy), 8.50 (d,
1H, 2-Hpy). Bis-picrate (yellow crystals): C46H62N8O14 (951.04) calcd: C, 58.09; H, 6.57; N, 11.78;
found: C, 57.83; H, 6.71; N, 11.58.
4.14. Acylation procedure with 2-pyridylacetic acid and borane reduction procedure
4.14.1. 16ꢀ-(2-Pyridylacet)amido-3-methoxy-estra-1,3,5(10)-triene-17ꢀ-ol 42
A solution of aminoalcohol 3 (903 mg, 3.0 mmol) in abs. CHCl3 (9 mL) was added to a stirred
mixture of 2-pyridylacetic acid hydrochloride (2.08 g, 12 mmol), abs. CHCl3 (15 mL), triethylamine
(1.22 g, 12 mmol) and N,N0-carbonyldiimidazole (1.94 g, 12 mmol). After 18 h at room temperature
water was added and the mixture was stirred for 2 h. The organic phase was separated, washed
three times with water, dried and evaporated. Crystallization with ethyl acetate gave 650 mg of 42
as white crystals and 450 mg of 42 after column chromatography on silica gel with ethyl acetate
and ethyl acetate:CH3OH (95:5 to 50:50). Yield of 42: 1.10 g (79%), white crystals (crystals with
0.5 mol ethyl acetate). M.p. 80±2ꢀC, 98±102ꢀC (solidi®cation), 180±185ꢀC; ‰ꢂŠ2D0=+38 (c=1.0,
1
CHCl3); H NMR (CDCl3): ꢁ=0.73 (s, 3H, 18H3), 2.82 (m, 2H, 6-H2), 3.72±3,75 (m+s, 6H,
17a-H, COCH2Py and OCH3), 4.29 (m, 1H, 16a-H), 6.60±6.70 (s+d, 2H, 4-H and 2-H), 7.17±7.26

2178
M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
(m, 2H, 1-H and 3-Hpy or 5-Hpy), 7.48 (d, 1H, 3-Hpy or 5-Hpy), 7.64 (t, 1H, 4-Hpy), 8.51 (m, 1H,
2-Hpy). C26H32N2O3+12CH3COOC2H5 (464.60) calcd: C, 72.38; H, 7.81; N, 6.01; found: C, 72.58;
H, 7.56; N, 6.41. HRMS 420.2380 calcd: 420.2357 for C26H32N2O3.
4.14.2. 16ꢀ-N-[2-(2-Pyridyl)ethyl]amino-3-methoxy-estra-1,3,5(10)-triene-17ꢀ-ol 29
To a stirred solution of borane in THF (1 M, 10 mL, Fluka) a solution of steroid amide 42 (335
mg, 0.72 mmol) in abs. THF (6 mL) was slowly added (45 min). After 3 h at room temperature
the solution was heated to 60ꢀC for 4 h. Aqueous hydrochloric acid (6N, 10 mL) was then added
and the mixture was heated to 60ꢀC for 1 h under stirring. After cooling to room temperature,
aqueous KOH was added and the basic mixture was extracted three times with ether. The com-
bined organic phases were washed with H2O, dried and evaporated under reduced pressure. The
oily residue was crystallized with CH3OH giving 216 mg (74%) as white crystals. M.p. 132±
20
ꢀ
1
136 C; ‰ꢂŠD =+76 (c=1.0, CHCl3); H NMR (CDCl3): identical with the spectrum of oily 29,
obtained by reaction of 3 with 2-vinyl pyridine (Section 4.13.3).
4.14.3. 16ꢀ-(2-Pyridylacet)amido-3-methoxy-estra-1,3,5(10)-triene-17ꢂ-ol 43
Aminoalcohol 4 (301 mg, 81.0 mmol) was acylated with 2-pyridylacetic acid hydrochloride as
described for the aminoalcohol 3 (Section 4.14.1). Crystallization with ethyl acetate gave 330 mg
of 43 (71%, crystallization with 0.5 mol ethyl acetate) as white crystals. M.p. 98±100ꢀC (crystal
20
transformation), 156±160ꢀC (partially) and 166±168ꢀC; ‰ꢂŠD =+23 (c=0.88, CHCl3); H NMR
(CDCl3): ꢁ=0.74 (s, 3H, 18-H3), 2.82 (m, 2H, 6-H2), 3.54 (s, 1H, 17b-H), 3.72 (s, 2H, COCH2Py),
3.75 (s, 3H, OCH3), 3.82 (m, 1H, 16a-H), 6.61 (s, 1H, 4-H), 6.69 (q, 1H, 2-H), 7.17±7.26 (m, 2H,
1-H and 3-Hpy or 5-Hpy), 7.65 (m, 2H, 4-Hpy and 3-or 5-Hpy), 8.52 (m, 1H, 2-Hpy).
C26H32N2O3+12CH3COOC2H5 (464.60) calcd: C, 72.38; H, 7.81; N, 6.01; found: C, 71.98; H, 7.64;
N, 5.99. HRMS m/z 420.2385 (M+) calcd: 420.2357 for C26H32N2O3.
1
4.14.4. 16ꢀ-N-[2-(2-Pyridy)ethyl]amino-3-methoxy-estra-1,3,5(10)-triene-17ꢂ-ol 30
Steroid amide 43 (300 mg, 0.65 mmol) was reduced with borane in THF as described for the
reduction of 42. The oily residue was puri®ed by column chromatography at silica gel with ethyl
acetate giving impurities and CH3OH giving the steroid compound 30 (160 mg, 60%) as a
20
1
colourless oil; ‰ꢂŠD =+56.6 (c=0.9, pyridine); H NMR (CDCl3): identical with the spectrum of
30, obtained by reaction of 4 with 2-vinyl pyridine (Section 4.13.4).
4.14.5. 16ꢀ-N,N-Bis-[2-(2-pyridyl)ethyl]amino-3-methoxy-estra-1,3,5(10)-triene-17ꢀ-ol 49
A solution of 29 (307 mg, 0.75 mmol) in abs. CHCl3 (5 mL) was added to a stirred mixture of
2-pyridylacetic acid hydrochloride (520 mg, 3 mmol), abs. CHCl3 (5 mL), triethylamine (304 mg,
3 mmol) and N,N0-carbonyldiimidazole (486 mg, 3 mmol). After 18 h at room temperature the
mixture was worked up as described for the synthesis of 42 (Section 4.14.1). Column chromato-
graphy at silica gel with ethyl acetate (yellow nonsteroidal compounds) and ethyl acetate:CH3OH
1
(95:5 to 50:50) gave 291 mg (74%) of 48 (together with 17b-ester) as a colourless oil; H NMR
(CDCl3): ꢁ=0.80 (s, 3H, 18-H3), 2.76±3.13 (2Âm, 6H, 6-H2, CH2CH2Py), 3.72±3.88 (s+m, 6H,
OCH3, COCH2Py, 17a-H), 4.60 (m, 1H, 16a-H), 6.61±6.70 (s+d, 2H, 4-H and 2-H). HRMS m/z
507.2860 (M+-H2O) calcd: 507.2834 for C33H37N3O2.
Amide 48 (290 mg, 0.57 mmol) in abs. THF was reacted with borane in THF (1 M, 8 mL) as
described for the reduction of 42. The residue was puri®ed by column chromatography at silica

M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
2179
gel with ethyl acetate giving impurities and ethyl acetate:CH3OH (95:5 to 50:50) giving compound
49 (100 mg, 43%) as oily product; ‰ꢂŠ2D0=+30.5 (c=0.7, pyridine); 1H NMR (CDCl3): ꢁ=0.62 (s,
3H, 18-H3), 2.82 (m, 2H, 6-H2), 2.95 and 3.05 (2Âm, 8H, 2ÂCH2CH2Py), 3.30 and 3.41 (m+d,
AB, 2H, 16a-H and 17a-H), 3.75 (OCH3), 6.61±6.70 (s+q, 2H, 4-H and 2-H), 7.06±7.20 (m, 5H, 1-
H, 2-3-Hpy and 5-Hpy), 7.53±7.60 (m, 2H, 4-Hpy), 8.51 (2H, 2-Hpy). HRMS m/z 493.3096 (M+^H2O)
calcd: 493.3045 for C33H39N3O.
4.15. Reductive amination procedure for 3-methoxy-estra-1,3,5(10)-triene-17-one 13
4.15.1. 17ꢀ-N-[2-(2-Pyridyl)ethyl]amino-3-methoxy-estra-1,3,5(10)-triene 45
Compound 13 (2.60 g, 9.1 mmol), 2-(2-pyridyl)ethylamine (8 mL, 7.79 g, 63.8 mmol) and tri-
methyl orthoformat (25 mL) were heated at 80ꢀC for 20 h under stirring. After cooling and
addition of abs. CH3OH (120 mL) NaBH4 (2.5 g, 66 mmol) were added at 10ꢀC. After 30 min
CH3OH was removed under reduced pressure, CHCl3 was added and the mixture was washed
with aqueous NaCl-solution and water. The organic phase was dried and evaporated under
reduced pressure. The residue was dissolved in abs. ether, ®ltered and treated with gaseous HCl at
10ꢀC. The solid amine hydrochloride was isolated by ®ltration, washed with ether and recrystal-
lized from C2H5OH (2.64 g). Methanolic solution (ca. 200 mL) of the hydrochloride was treated
with aqueous KOH (2 g KOH, 20 mL H2O) under cooling and stirring. After 1 h at room tem-
perature ice/H2O was added and the precipitate isolated by ®ltration, washed with water and
dried in vacuum. Compound 45 (2.1 g, 59%): white solid, m.p. 124±126ꢀC. A sample was
recrystallized from isopropanol; m.p. 126±127ꢀC; ‰ꢂŠD20=+70 (c=1.1, CHCl3); 1H NMR (CDCl3):
ꢁ=0.67 (s, 3H, 18-H3), 2.65 (t, 1H, 17a-H), 2.81 (m, 2H, 6-H2), 2.94±3.04 (m, 4H, CH2CH2Py),
3.75 (s, 3H, OCH3), 6.60±6.70 (s and d, 4-H and 2-H), 7.07±7.18 (m, 3H, 1-H, 3-Hpy and 5-Hpy),
7.57 (m, 1H, 4-Hpy), 8.51 (m, 1H, 2-Hpy); 13C NMR (CDCl3): ꢁ=11.70 (18-C), 55.17 (19-C),
69.11 (17-C), 111.40 (2-C), 113.76 (4-C), 121.15 (3-Cpy), 123.26 (5-Cpy), 126.26 (1-C), 132.82 (10-
C), 136.26 (4-Cpy), 137.99 (5-C), 149.28 (2-Cpy), 157.38 (3-C), 160.46 (6-Cpy). C26H34N2O (390.57)
calcd: C, 79.96; H, 8.77; N, 7.17; found: C,79.63; H, 8.93; N, 7.03.
(E)-17-N-[2-(2-Pyridyl)ethyl]imino-3-methoxy-estra-1,3,5(10)-triene 44: The imine 44 can be
isolated before the reduction procedure by cooling the reaction mixture and ®ltration of the
crystalline imine: 3.29 g (93%). M.p. 158±161ꢀC; ‰ꢂŠD20=+66 (c=0.93, CHCl3); 1H NMR
(CDCl3): ꢁ=0.75 (s, 3H, 18-H3), 2.83 (m, 2H, 6-H2), 3.06±3.66 (2Âm, 4H, CH2CH2Py), 3.75 (s,
3H, OCH3), 6.60±6.71 (s, m, 2H, 4-H and 2-H), 7.05±7.21 (m, 3H, 1-H, 3-Hpy and 5-Hpy), 7.53
(m, 1H, 4-Hpy), 8.50 (m, 1H, 2-Hpy). X-Ray analysis: 17CˆN E-con®guration. C26H32N2O
(388.55) calcd: C, 80.37; H, 8.30; N, 7.21; found: C, 80.14; H, 8.48; N, 7.15.
4.15.2. 17ꢀ-N-[3-(1-Imidazolyl)propyl]amino-3-methoxy-estra-1,3,5(10)-triene 51
Ketone 13 (3.27 g, 11.5 mmol), 1-(3-aminopropyl)imidazol (3.0 mL, 25.1 mmol) and triethyl
orthoformate were reacted for 12 h using an ultrasonic apparatus. The clear solution was diluted
with abs. ethanol and NaBH4 (1.0 g, 26.4 mmol) was then added under continuous stirring. After
12 h, the ethanol was removed under reduced pressure and ether and water were then added. The
organic phase was separated, washed and dried. The etheric solution was treated with gaseous
HCl and the hydrochloride isolated by ®ltration (4.86 g). Aqueous KOH (5.0 g KOH, 30 mL
H2O) was added to a methanolic solution of this hydrochloride (50 mL). The resulting mixture
was then poured onto ice/H2O (250 mL). The precipitate was ®ltered o€, washed with water and
dried giving 4.27 g of amine 51 (94%) as a white powder. M.p. 95±97ꢀC; ‰ꢂŠD20=+58 (c=0.94,

2180
M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
1
CHCl3); H NMR (CDCl3): ꢁ=0.69 (s, 3H, 18-H3), 2.53±2.61 (m, 3H, 17a-H and N-CH2), 2.81
(m, 2H, 6-H2), 3.75 (s, 3H, OCH3), 4.03 (m, 2H, CH2-N), 6.59±6.69 (2Âm, 2H, 4-H and 2-H),
6.90 (s, 1H, Him), 7.03 (s, 1H, Him), 7.17 (m, 1H, 1-H), 7.41 (s, 1H, Him). C25H35N3O (393.57)
calcd: C, 76.29; H, 8.96; N, 10.68; found: C, 75.83; H, 8.93; N, 10.59.
4.15.3. 17ꢀ-N-[3-(1-Morpholino)propyl]amino-3-methoxy-estra-1,3,5(10)-triene 52
Compound 13 (2.74 g, 9.6 mmol), 1-(3-aminopropyl)morpholine (2,8 mL, 19.2 mmol) and
triethyl orthoformate (10 mL) were reacted as described for the synthesis of 51. Reduction with
NaBH4 (1.0 g, 26.4 mmol) as described (Section 4.15.2) gave the amine 53 (3.65 g, 92%) as a
20
white powder. M.p. 110±112ꢀC; ‰ꢂŠD =+64 (c=0.96, CHCl3); H NMR (CDCl3): ꢁ=0.71 (s, 3H,
18-H3), 2.58 (m, 1H, 17a-H), 2.67 (m, 4H, 2-NCH2), 2.81 (m, 2H, 6-H2), 3.68±3.75 (m+s, 7H,
2ÂOCH2, OCH3), 6.59±6.69 (2Âm, 4-H and 2-H), 7.18 (m, 1H, 1-H). C26H40N2O2 (412.61) calcd:
C, 75.68; H, 9.77; N, 6.79; found: C, 75.69; H, 10.00; N, 6.66.
1
4.15.4. 17ꢀ-N,N-Bis-[2-(2-Pyridyl)ethyl]amino-3-methoxy-estra-1,3,5(10)-triene 47
Compound 45 (2.11 g, 5.4 mmol) in abs. CHCl3 (8 mL) was acylated with 2-pyridylacetic acid
hydrochloride (1.8 g, 10 mmol), triethylamine (1.1 g, 10 mmol), and N,N0-carbonyldiimidazole
(1.7 g, 10 mmol) in abs. CHCl3 (15 mL) as described for the synthesis of 42 (Section 4.14.1). After
18 h CHCl3 and water were added. The organic phase was separated and washed three times with
water, dried and evaporated. The residue was puri®ed by column chromatography at silica gel
with ethyl acetate (yellow nonsteroidal compounds) and ethyl acetate:CH3OH (95:5 to 70:30)
giving amide 46 as white foam [2.45 g, 89%, mixture of (Z)- and (E)-amide]; ‰ꢂŠ2D0=^6 (c=0.9,
1
CHCl3); H NMR (CDCl3): ꢁ=0.66 and 0.78 (2Âs, 3H, 18-H3), 2.82 (m, 2H, 6-H2), 2.8±3.7
(several m, 4H, CH2CH2Py), 3.75 (s, 3H, OCH3), 3.90±4.15 (m, 2.6H, COCH2Py and 17a-H
partially), 4.62 (m, 0.4H, 17a-H partially), 6.59±6.70 (m, 2H, 4-H and 2-H), 7.04±7.20 (m, 4H, 1-H
and 3ÂHpy), 7.52 (m, 1H, Hpy), 7.60±7.66 (m, 2H, 2ÂHpy), 8.50 (m, 2H, 2Â2-Hpy). HRMS m/z
509.30380 (M+), calcd: 509.30376 for C33H39N3O2.
The amide 46 (509 mg, 1 mmol), dissolved in abs. THF (8 mL), was slowly added to a borane
solution in THF (1 M, 10 mL). After 3 h at room temperature the solution was heated to 60ꢀC for
7 h. The work-up procedure as described for the reduction of 42 gave a yellow oily product (466
mg), which was puri®ed by column chromatography at silica gel with ethyl acetate (nonsteroidal
compounds) and CH3OH giving the steroid compound 47 as a colourless oil (345 mg, 70%);
20
1
‰ꢂŠD =+85 (c=0.2, CHCl3); H NMR (CDCl3): ꢁ=0.68 (s, 3H, 18-H3), 2.71 (t, 1H, 17a-H),
2.81 (m, 2H, 6-H2), 2.91±3.07 (m, 8H, 2ÂCH2CH2Py), 3.75 (s, 3H, OCH3), 6.59±6.96 (d+q,
2H, 4-H and 2-H), 7.07±7.17 (m, 5H, 2Â3-Hpy and 5-Hpy, 1-H), 7.56 (m, 2H, 2Â4-Hpy), 8.50
(2Â2-Hpy). C33H41N3O (495.70) calcd: C, 79.96; H, 8.34; N, 8.48; found: C, 79.14; H, 8.54; N, 8.03.
4.16. Procedures for the synthesis of mixed ligands 50 and 53
4.16.1. Michael reaction of 34 and methyl acrylate to 50
N-Pyridylethylamino compound 34 (100 mg, 0.197 mmol), methyl acrylate (20 mg, 0.232
mmol) and abs. ethanol (10 mL) were heated under re¯ex for 20 h. After evaporation under
reduced pressure the residue was puri®ed by MPLC.
2a-N-(2-Methoxycarbonylethyl)-N-[2-(2-pyridyl)ethyl]amino-5a-cholestane-3b-ol 50, 96 mg
(85%), colourless oil; ‰ꢂŠ2D0=+28 (c=0.67, CHCl3). UV (CH3OH): lmax (lg ")=261 (3.6180); H
1
NMR (CDCl3): ꢁ=0.62 (s, 3H, 18-H3), 0.79 (s, 3H, 19-H3), 0.84 (d, 6H, 26-H3 and 27-H3), 0.88

M. Gonschior et al. / Tetrahedron: Asymmetry 11 (2000) 2159±2182
2181
3
(d, 3H, J=6.6 Hz, 21-H3), 2.18 (m, 2H, CH2CH2), 2.50 (m, 2H, 2b-H and CH2CH2), 2.84 (m,
5H, CH2CH2), 3.32 (m, 1H, 3a-H), 3.57 (s, 3H, OCH3), 7.10 (m, 2H, 3-Hpy and 5-Hpy), 7.55 (t,
1H, J=7.7 Hz, J=1.7 Hz, 4-Hpy), 8.50 (d, 1H, J=4.0 Hz, 2-Hpy). HRMS m/z 576.4520
3
4
3
(M+^H2O), calcd: 576.4538 for C38H60N2O2.
4.16.2. 17ꢀ-N-[2-(2-Pyridyl)ethyl]-N-[3-(1-imidazolyl)propyl]amino-3-methoxy-estra-1,3,5(10)-
triene 53
Steroid 51 (1.97 g, 5.0 mmol) in abs. CHCl3 (3 mL) was acetylated with 2-pyridylacetic acid
hydrochloride (1.11 g, 6.4 mmol), triethylamine (1.7 mL, 12.2 mmol) and N,N0-carbonyldiimidazol
(1.04 g, 6.4 mmol) as described for the synthesis of 47. Puri®cation was accomplished with column
chromatography on silica gel with ethyl acetate (600 mL, solution of nonsteroidal compounds)
and ethyl acetate:CH3OH (80:20 to 50:50) giving 1.87 g (73%) of 17b-pyridylacetamide as a
colourless oil (1H NMR: ꢁ=0.55 and 0.68, 3H, 18-H3, Z/E-mixture); 568 mg (1.1 mmol) were
directly reduced with borane in THF as described for the synthesis of 47 (Section 4.15.4) giving
413 mg (75%) of 53 as a colourless oil.; ‰ꢂŠ2D0=+53 (c=0.52, CHCl3); 1H NMR (CDCl3): ꢁ=0.71
(s, 3H, 18-H3), 2.59±2.65 (m, 3H, NCH2 and 17a-H), 2.81±2.99 (m, 6H, 6-H2 and CH2CH2Py),
3.75 (s, 3H, OCH3), 3.94 (m, 2H, CH2N), 6.59±6.70 (2Âm, 2H, 4-H and 2-H), 6.90 (s, 1H, Him),
7.04±7.18 (m, 4H, 1-H, 3-Hpy, 5-Hpy, Him), 7.45 (s, 1H, Him), 7.56 (m, 1H, 4-Hpy), 8.50 (d, 1H,
2-Hpy). Tris-picrate: C50H51N13O22 (1186.03) calcd: C, 50.64; H, 4.33; N, 15.35; found: C, 51.20;
H, 4.69; N, 14.13. HRMS (ESI in CH3OH) m/z (M+1): 499.3443; calcd: 499.3437 for C32H49N4O.
Financial support from the Deutsche Forschungsgemeinschaft (Sonderforschungsbereich 436)
is gratefully acknowledged. We would also like to thank the Schering AG for their gift of ster-
oidal compounds.
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