Synthesis of 16,17-seco-steroids with iminomethyl-2-pyridine and aminomethylene-2-pyridine structures as chiral ligands for copper ions and molecular oxygen activation

Article abstract of DOI:10.1016/S0957-4166(03)00539-1

Starting from 16-oximino-3-methoxy-estra-1.3.5(10)-trien-17-one, the 16,17-seco-13α-carbaldehyde with a 16-nitrile function and its corresponding carboxylic acid have been synthesized via a Beckmann fragmentation. The corresponding 13α-amine is available by Curtius degradation of the carboxylic acid. Condensation of the carboxaldehyde with 2-(aminomethyl)pyridine and the primary amine with pyridine-2-carboxaldehyde gave the corresponding iminomethyl-2-pyridine and the aminomethylene-2-pyridine compounds. Copper-mediated ligand hydroxylations with molecular oxygen were not successful. Reasons for this are discussed.

Full text of DOI:10.1016/S0957-4166(03)00539-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 2705–2715
Synthesis of 16,17-seco-steroids with iminomethyl-2-pyridine and
aminomethylene-2-pyridine structures as chiral ligands for copper
ions and molecular oxygen activation
Ange´la Magyar,a Bruno Scho¨necker,b,* Ja´nos Wo¨lfling,a Gyula Schneider,a Wolfgang Gu¨ntherb and
Helmar Go¨rlsc
aDepartment of Organic Chemistry, University of Szeged, Do´m te´r 8, H-6720 Szeged, Hungary
bInstitute of Organic Chemistry and Macromolecular Chemistry, Friedrich Schiller University Jena, Lessingstraße 8,
D-07743 Jena, Germany
cInstitute of Inorganic and Analytical Chemistry, Friedrich Schiller University Jena, Lessingstraße 8, D-07743 Jena, Germany
Received 13 June 2003; accepted 7 July 2003
Abstract—Starting from 16-oximino-3-methoxy-estra-1.3.5(10)-trien-17-one, the 16,17-seco-13a-carbaldehyde with a 16-nitrile
function and its corresponding carboxylic acid have been synthesized via a Beckmann fragmentation. The corresponding
13a-amine is available by Curtius degradation of the carboxylic acid. Condensation of the carboxaldehyde with 2-
(aminomethyl)pyridine and the primary amine with pyridine-2-carboxaldehyde gave the corresponding iminomethyl-2-pyridine
and the aminomethylene-2-pyridine compounds. Copper-mediated ligand hydroxylations with molecular oxygen were not
successful. Reasons for this are discussed.
© 2003 Elsevier Ltd. All rights reserved.
16-position in yields of 16–33% (Fig. 1).14 Using 17a-
aza-N-2-(2-pyridylethyl)amino compounds, b-hydroxyl-
ation in the 16a-position (5%) and in the neighborhood
of the pyridine ring [(R)- and (S)-alcohol, 8.5 and 5.5%]
took place for the 13b-series (trans-fused piperidine,
Fig. 1); no b-hydroxylation for the 13a-series (cis-fused
piperidine) could be found. Moreover, the preparation
of the oxidizing complex has an influence on its oxida-
tion behavior.15
1. Introduction
Copper-containing enzymes such as dopamine-b-
hydroxylase are fascinating models for selective hydrox-
ylations with simpler copper complexes and molecular
oxygen.1–6 The quantitative b-hydroxylation of benzylic
positions of tridentate or bidentate ligands possessing a
(2-pyridyl)ethylamino unit is possible.7–11 Hydroxyla-
tion of unactivated CH2 groups in these ligands, how-
ever is much more difficult. Re´glier et al. have shown
that n-propyl or cyclopentyl groups can be b-hydroxyl-
ated to secondary alcohols in 10 and 13% with triden-
tate ligands. The main products of this reaction are
alcohols formed by b-hydroxylation of the CH2 group
in the neighborhood of the pyridine ring (64 and
42%).12 In order to investigate the stereochemical
requirements for such hydroxylations we have
employed a conformationally restricted chiral steroid
core possessing tri- and bidentate ligands.13 With biden-
tate 17b-N-2-(2-pyridylethyl) and (2-pyridylmethyl)
amino groups we could achieve b-hydroxylation in the
In order to investigate conformationally more restricted
bidentate ligands, we employed the simple to prepare
17-iminoalkyl-2-pyridine steroids (condensation of the
17-ketone with 2-aminoalkylpyridines) in the hydroxyl-
ation procedure. For these ligands, a regio- and
stereoselective g-hydroxylation of a nonactivated CH2
group in 12b-position could be observed in practical
yields of 40–50% (Fig. 1).14 A further advantage of
these compounds is the simple hydrolysis of the imino
bond after the hydroxylation giving the 12b-hydroxy-
17-ketones.
In order to gain further insight into the behavior of
such iminoalkylpyridine ligands, we became interested
in synthesizing the steroidal 16,17-seco-aldehyde A
* Corresponding author. Fax: +49-3641-948292; e-mail: c8scbr@
uni-jena.de
0957-4166/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00539-1

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A. Magyar et al. / Tetrahedron: Asymmetry 14 (2003) 2705–2715
Figure 1. Examples for b- and g-hydroxylations.
(Fig. 2). Condensation with 2-aminomethylpyridine
should then yield the imino ligand B. A can also be
oxidized to give the corresponding carboxylic acid C,
which possibly can be degradated to the interesting
primary 13a-amine D which possesses a stereogenic
tertiary center. Condensation of D with pyridine-2-car-
boxaldehyde led to another interesting type of
aminomethylene pyridine ligands E. We now investigate
these isomeric ligands in terms of their copper complex-
ation, oxygen activation and ligand hydroxylation.
compound 3. Beckmann fragmentation finally fur-
nished the seco-17-aldehyde 416,17 (Scheme 1). The car-
boxylic acid 5 could be obtained in a satisfactory yield
by Jones oxidation. The lactone 6 was isolated as a
non-polar side product. The structure and absolute
configuration of this product was determined by X-ray
analysis as a 9a-lactone (Fig. 3). Recently we reported
the formation of a similar lactone.19 6 is the sole
product obtained when an excess of Jones reagent is
employed. It could very well be that mixed chromic
acid 13a-carboxylic acid anhydride is able to oxidize
the 9a-benzylic position in an interesting intramolecular
regio- and stereoselective d-hydroxylation procedure. A
few intermolecular reactions using chromyl acetate20 or
chromyl trifluoracetate21 have been reported in the
literature.
2. Results and discussion
We then synthesized the desired 16,17-seco-17-aldehyde
4 with a 16-nitrile function according to a literature
procedure16,17 starting with 3-O-methyl estrone 1, a
known pharmaceutical. Then the thus obtained 16,17-
dione 16-oxime 218 was reduced to the 17b-hydroxy
The carboxylic acid 5 could also be obtained directly
from 2 using a Beckmann fragmentation procedure
Figure 2. Types of 16,17-seco steroids.

A. Magyar et al. / Tetrahedron: Asymmetry 14 (2003) 2705–2715
2707
Scheme 1. Synthesis of 16,17-seco-steroids. Reagents and conditions: (a) i-amyl nitrite/KOtBu/tBuOH; (b) NaBH4/MeOH; (c)
pTsCl/pyridine; (d) Jones reagent; (e) TiCl4/CH2Cl2; (f) TiCl3/HCl/EtOH.
Figure 3. Molecular structure of 6.
(Scheme 1). Compound 2 could be transformed under
heating to 5 (74%) by employing p-tosyl chloride and
pyridine.22 The carboxylic acid anhydride 7 could be
isolated as a side product (7%). The fragmentation of 2
ketol 8.25–28 The structure of 8 was determined by X-ray
analysis (Fig. 4).
For the synthesis of the desired primary amine 11, a
one-pot procedure starting from the carboxylic acid 5
with diphenylphosphoryl azide,29,30 should give the iso-
cyanate 9, which can then be hydrolyzed to 11 seems to
be attractive. Using this Curtius degradation procedure,
we could isolate the crystalline isocyanate 9 in 75%
yield. A simple reaction with CH3OH was possible,
23
was also successful with the Lewis acid TiCl4 in
dichloromethane. This resulted in a yield of 73% for 5.
24
Reaction of 2 with TiCl3 in ethanol gave only the
17b-hydroxy-16-ketone 8 in a yield of 68% (cleavage of
the oxime function and reduction of the 17-ketone of
2). This procedure is a convenient way to synthesize the

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A. Magyar et al. / Tetrahedron: Asymmetry 14 (2003) 2705–2715
Figure 4. Molecular structure of 8.
which led to the urethane 10 in a high yield. In contrast
to this, the hydrolysis of 9 to 11 was problematic.31,32
Quite a few products were detected by TLC in both
acidic and alkaline conditions. It seems that the nitrile
group is involved in the reaction. Several intramolecu-
lar cyclisation reactions are possible. We finally suc-
ceeded in transforming of 9 into 11 in a nearly
quantitative yield by a direct reaction with concentrated
hydrobromic acid followed by treatment with sodium
hydroxide (Scheme 2). In summary, 5 can be conve-
niently employed to obtain the interesting primary
amine 11 which contains a stereogenic tertiary center
and an additional nitrile function.
hydroxylation in the positions 12, 14 and 18, depending
on the conformation of the active complex.14 The X-ray
structure of 15 shows a conformation that would result
in a preference for a 18-hydroxylation (13b-CH3
group). The chelating part of the iminomethylene-2-
pyridine compound 12 is isomeric with the correspond-
ing functionality in 15. The CꢀN double bond is
conjugated with the pyridine ring. Only the 15-position
(CH2 group in neighborhood to the CN group) is close
enough for a g-hydroxylation. The influence of the
cyano group is difficult to estimate. It could activate the
neighboring CH2 group (C-15) for hydroxylation; on
the other hand, participation in the complexation of
copper could prevent the binding and activation of
molecular oxygen.
The aldehyde 4 and the primary amine 11 are starting
materials for the synthesis of chiral ligands (Scheme 2)
suitable for the binding of copper ions. 4 was con-
densed with 2-(aminomethyl)pyridine in order to obtain
the iminomethyl-2-pyridine compound 15. The E-
configuration of the CꢀN bond was determined by
NMR-NOESY experiments and by X-ray analysis (Fig.
5). The secondary amine 16 with a pyridylmethyl group
could be obtained by reduction with NaBH4. Conden-
sation of 4 with 2-aminopyridine was successful using
BF3·OEt2 in CH2Cl2. Direct reduction of 17 with
NaBH4 yielded the secondary 2-aminopyridine 18.
Starting with the primary amine 11, the
aminomethylene-2-pyridine compound 12 could be
obtained quantitatively by reaction with pyridine-2-car-
boxaldehyde. The E-configuration of the CꢀN double
bond was also determined by NMR-NOESY experi-
ments. By reduction with NaBH4, the pyridylmethyl-
amino compound 13 was obtained as an oil in a high
yield. The bis-hydrochloride 14 is a crystalline com-
pound. We then investigated the ability of the
aminomethylene-2-pyridine compound 12 and the imi-
nomethyl-2-pyridine compound 15 to complex with
copper(I) ions. These complexes were then tested to see
if they react with molecular oxygen. The chelating part
of 15 resembles the ring-imino compound (see Fig. 1)
and therefore could possibly induce an interesting g-
Compound 15 was reacted with Cu(I)(CH3CN)4PF6 in
CH2Cl2 to obtain a yellow complex. Reaction with O2
then resulted in a green solution. After three days,
decomplexation was carried out with aqueous ammo-
nia. The isolated mixture was investigated with spectro-
scopic methods, especially with mass spectroscopy
(ESI). Main peaks at 406 (15+H2O+H) and 315 (4+
NH3+H) and a further peak at 388 (15+H) indicated
partial hydrolysis and ammonolysis of the imino group
and the cyano group but not to hydroxylated products.
After chromatography the unchanged ligand 15 (34%)
and the hydrolyzed ligand 4 (12%) were isolated, as the
only products. More polar fractions furnished mixtures
of unseparable compounds. The same procedure with
12 gave a brown copper(I) complex solution, which was
changed to a green–brown slurry upon exposure to O2.
In this case, main peaks at 396 (12+Na), 374 (12+H)
and 295 (11+H) could be detected by MS (ESI). After
preparative TLC, 12 (56%) could be isolated as the only
product. The results demonstrated that the 16-nitrile
function of 16,17-seco steroids has some disadvantages
in copper-mediated hydroxylation procedures. It is not
fully stable under the used conditions and can also
prevent a successful hydroxylation procedure.

A. Magyar et al. / Tetrahedron: Asymmetry 14 (2003) 2705–2715
2709
Scheme 2. Synthesis of amino- and imino-seco-steroids. Reagents and conditions: (a) diphenylphosphoryl azide, NEt3, toluene; (b)
CH3OH/KOH; (c) conc. HBr, NaOH; (d) pyridine-2-carboxaldehyde, CH3OH; (e) NaBH4, CH3OH; (f) HCl, ether; (g)
2-(aminomethyl)pyridine, CH3OH/THF; (h) 2-aminopyridine, CH2Cl2, Et2O·BF3.
3. Conclusions
neighborhood of the complexing moiety, which could
possibly prevent oxygen activation. Further studies
with similar ligands which do not contain a nitrile
function are necessary to give more insight into these
interesting reactions.
Comparison of the conformationally restricted 17-imi-
nomethyl-2-pyridine ligand14 (Fig. 1, regio- and
stereoselective copper-mediated 12b-hydroxylation with
molecular oxygen14) with the more flexible 17-imino-
methyl-2-pyridine ligand 15 of the 16,17-secosteroid
series [Scheme 2, no hydroxylation could be observed
starting with Cu(I) or Cu(II) complexes] shows that a
predefined arrangement for the CꢁH bond and the
active copper–oxygen complex is important for a suc-
cessful hydroxylation procedure. In addition, the 13a-
4. Experimental
4.1. General
Melting points were measured on Boe¨tius micromelting
point apparatus (corrected values). Optical rotations
were measured with a photoelectronic polarimeter Pola-
mat A (Carl Zeiss Jena) in chloroform at 546 and 578
nm and extrapolated to 589 nm (c 1 g 100−1 ml−1). IR
aminomethylene-2-pyridine
ligand
12
of
the
16,17-secosteroid series (Scheme 2) could not be
hydroxylated. It should also be pointed out that the
ligands 12 and 15 possess a nitrile function in the

2710
A. Magyar et al. / Tetrahedron: Asymmetry 14 (2003) 2705–2715
Figure 5. Molecular structure of 15.
spectra were recorded on an Impact 400 spectrometer
(NICOLET) by ATR.
−90°C, Z=2, rcalcd=1.281 g cm−3, m (Mo–Ka)=0.86
cm−1, F(000)=332, 3112 reflections in h(−8/8), k(−10/
9), l(−19/19), measured in the range 3.63°5U527.45°,
completeness Umax=96.5%, 3112 independent reflec-
tions, 2934 reflections with Fo>4s(Fo), 292 parameters,
1 restraint, R1obs=0.037, wR2obs=0.096, R1all=0.040,
1H and 13C NMR spectra were recorded on a Bruker
spectrometer DRX 400 (1H NMR 400 MHz using TMS
as internal standard, 13C NMR 100 MHz using CDCl3
triplet as reference, d 77.0 ppm) in CDCl3 (if not
otherwise given). Signals were assigned by DEPT,
COSY-DQF, TOCSY and NOESY. Mass spectra were
recorded on an AMD 402 Intectra instrument with
electron impact (EI), direct electron impact (DEI) and
electro spray (ESI) ionization with 70 eV. Elemental
analyses were determined on CHNO-Rapid (HER-
AEUS) or CHNS-932 (LECO) instruments. All reac-
tions were monitored by TLC aluminum sheets, silica
gel 60 F254 (Merck), 0.2 mm, detection by UV (254 nm)
and spraying with a solution of P2O5·24MoO3·H2O (2.5
g/50 ml 42% H3PO4) and heating at 170°C. Solvents
were dried, purified and distilled according to conven-
tional methods.
wR2all=0.098,
GOOF=1.049,
Flack-parameter
−0.1(11), largest difference peak and hole: 0.171/−0.137
−3
,
e A .
Crystal data for 8:37 C19H24O3, Mr=300.38 g mol−1,
colourless prism, size 0.04×0.04×0.03 mm3, monoclinic,
space group P21, a=6.9232(2), b=8.1608(3), c=
3
,
,
13.9745(6) A, b=91.866(1)°, V=789.12(5) A , T=
−90°C, Z=2, rcalcd=1.264 g cm−3, m (Mo–Ka)=0.84
cm−1, F(000)=324, 3050 reflections in h(−8/8), k(−9/
10), l(−18/18), measured in the range 2.92°5U5
27.48°, completeness Umax=99.2%, 3050 independent
reflections, 2549 reflections with Fo>4s(Fo), 203
parameters, 1 restraint, R1obs=0.039, wR2obs=0.094,
R1all=0.053, wR2all=0.1024, GOOF=1.013, Flack-
parameter 0.2(12), largest difference peak and hole:
0.162/−0.145 e A .
4.2. Crystal structure determination
−3
,
The intensity data for the compounds were collected on
a Nonius KappaCCD diffractometer, using graphite-
monochromated Mo–Ka radiation. Data were corrected
for Lorentz and polarization effects, but not for
absorption effects.33,34
Crystal data for 15:37 C25H29N3O, Mr=387.51 g mol−1,
colourless prism, size 0.04×0.03×0.03 mm3, monoclinic,
space group P21, a=11.2252(5), b=8.1233(4), c=
3
,
,
12.0500(5) A, b=106.830(3)°, V=1051.72(8) A , T=
−90°C, Z=2, rcalcd=1.224 g cm−3, m (Mo–Ka)=0.75
cm−1, F(000)=416, 7571 reflections in h(−13/14), k(−
10/10), l(−14/15), measured in the range 2.94°5U5
27.39°, completeness Umax=98.9%, 4661 independent
reflections, Rint=0.053, 3177 reflections with Fo>4s(Fo),
The structures were solved by direct methods
(SHELXS35) and refined by full-matrix least-squares
techniques against Fo (SHELXL-9736). For compound
2
6 and for the hydroxy-group O2 of 8, the hydrogen
atoms were located by difference Fourier synthesis and
refined isotropically. All other hydrogen atoms were
included at calculated positions with fixed thermal
parameters. All nonhydrogen atoms were refined
anisotropically.36 XP (SIEMENS Analytical X-ray
262 parameters, 1 restraint, R1obs=0.077, wR2
=
obs
0.119, R1all=0.129, wR2all=0.147, GOOF=1.085,
Flack-parameter 4(3), largest difference peak and hole:
−3
,
0.255/−0.267 e A .
Instruments,
representations.
Inc.)
was
used
for
structure
4.3. 3-Methoxy-16,17-secoestra-1,3,5(10)-trien-16-
nitrile-17-oic acid 5
Crystal data for 6:37 C19H21NO3, Mr=311.37 g mol−1,
colourless prism, size 0.18×0.12×0.10 mm3, monoclinic,
(a) Aldehyde 4 (3.41 g, 11.5 mmol) was dissolved in
acetone (250 ml) and cooled to 0°C. To this stirred
solution, Jones reagent (11.5 ml, 8N CrO3 solution in
conc. H2SO4) was added dropwise. After 20 min, a
space group P21, a=7.1427(2), b=7.7100(3), c=
3
,
,
14.9150(5) A, b=100.535(2)°, V=807.53(5) A , T=

A. Magyar et al. / Tetrahedron: Asymmetry 14 (2003) 2705–2715
2711
OMe), 6.64 (d, J=2.7 Hz, 2H, 2×4-H), 6.72 (dd, J=
8.7, 2.7 Hz, 2H, 2×2-H), 7.16 (d, J=8.7 Hz, 2H,
2×1-H) ppm; 13C NMR (CDCl3, 125 MHz): d 15.2
(C-18), 18.4 (C-15), 48.8 (C-13), 55.2 (3-OMe), 112.1
(C-2), 113.6 (C-4), 118.6 (C-16, C=N), 126.2 (C-1),
130.6 (C-10), 137.3 (C-5), 158.0 (C-3), 173.3 (C-17,
COO) ppm; IR (ATR): 2246 (CꢂN), 1803, 1739, 1609
cm−1; MS (ESI) m/z (%): 631 (100) [M+Na]+. Anal.
calcd for C38H44O5N2 (608.78): C, 74.97; H, 7.29; N,
4.60. Found: C, 74.64; H, 7.16; N, 4.50%.
small amount of i-propanol was added and stirring
was continued for further 10 min. H2O/ice (250 ml)
was then poured onto the reaction mixture and it was
extracted with CH2Cl2. The combined organic phases
were washed with H2O and dried (Na2SO4). Evapora-
tion of the solvent afforded a mixture of 5 and 6
(3.27 g). Chromatography on silica gel with 5 and
10% t-butyl methyl ether/CH2Cl2 yielded the lactone
6 (0.39 g, 11%) as the less polar compound and 5
(2.44 g, 68%). 5 Mp 160–165°C (methanol): [a]2D0=
+78 (c 1, CHCl3); 1H NMR (400 MHz, CDCl3): d
1.30 (s, 3H, 18-H3), 2.91 (m, 2H, 6-H2), 3.77 (s, 3H,
OMe), 6.63 (d, J=2.6 Hz, 1H, 4-H), 6.72 (dd, J=8.6,
2.6 Hz, 1H, 2-H), 7.17 (d, J=8.6 Hz, 1H, 1-H), ppm;
13C NMR (100 MHz, CDCl3): d 15.1 (C-18), 18.5
(C-15), 47.1 (C-13), 55.2 (3-OMe), 112.0 (C-2), 113.6
(C-4), 118.8 (C-16, CꢂN), 126.3 (C-1), 131.0 (C-10),
137.4 (C-5), 157.9 (C-3), 182.3 (C-17, COOH) ppm;
IR (ATR): 2245 (CꢂN), 1695 (acid CꢀO) cm−1; MS
(ESI) m/z (%): 368 (15) [M+Na+MeOH]+, 336 (100)
[M+Na]+; HRMS m/z: found 336.15616 [M+Na]+,
calcd: 336.15756 for C19H23NO3Na. Anal. calcd for
C19H23NO3 (313.40): C, 72.82; H, 7.40; N, 4.47.
Found: C, 73.44; H, 7.14; N, 4.24%.
(c) 2 (223 mg, 0.7 mmol) was dissolved in abs.
dichloromethane (5 ml) under argon at 0°C and TiCl4
(0.2 ml, 2.1 mmol) was added. The solvent became
dark brown. It was stirred for 8 h at rt and refluxed
for 10 h. Wet ether (1 ml) and water (10 ml) was
added to the cold reaction mixture, which was
extracted three times with CH2Cl2, dried (Na2SO4)
and concentrated in vacuo to yielding crude 5 (214
mg, 96%). Preparative TLC (silica gel) with methanol/
dichloromethane (1:9) affording 5 (163 mg, 73%),
which is identical with the product of the Jones oxi-
dation of aldehyde 4 (see above).
4.4. 9a-Hydroxy-3-methoxy-estra-1,3,5(10)-trien-16-
nitrile-17-oic acid 9,17-lactone 6
9a-Hydroxy-3-methoxy-16,17-secoestra-1,3,5(10)-trien-
16-nitrile-17-oic acid 9,17-lactone 6
Compound 4 (100 mg, 0.34 mmol) was dissolved in
acetone (83 ml). To the stirred solution, Jones reagent
(1 ml, 8N CrO3 solution in conc. H2SO4) was added
dropwise at rt. After 20 min, a few drops of i-
propanol was added and stirring was continued for
further 10 min. H2O/ice (10 ml) was poured onto the
reaction mixture and it was extracted three times with
CH2Cl2. The combined organic phases were washed
with H2O and dried (Na2SO4). Evaporation of the
solvent afforded 95.6 mg product (91%; the conversion
to 6 was total according to the TLC). Chromatogra-
phy on silica gel with t-butyl methyl ether/CH2Cl2;
5:95 yielded 60.8 mg of 6 (58%), identical with the side
product described above (see Section 4.3.a).
1
Mp 235–242°C (acetone): [a]2D0=+92 (c 1, CHCl3); H
NMR (400 MHz, CDCl3): d 1.22 (s, 3H, 18-H3), 2.82
(m, 2H, 6-H2), 3.77 (s, 3H, OMe), 6.63 (d, J=2.5 Hz,
1H, 4-H), 6.80 (dd, J=8.8, 2.6 Hz, 1H, 2-H), 7.43 (d,
J=8.8, 1H, 1-H) ppm; 13C NMR (100 MHz, CDCl3):
d 17.4 (C-15), 18.3 (C-18), 40.0 (C-13), 55.3 (3-OMe),
113.2 (C-4 and C-2), 118.2 (C-16, C=N), 126.3 (C-
10), 129.1 (C-1), 138.9 (C-5), 159.8 (C-3), 176.2 (C-17,
COO) ppm; IR (ATR): 2253 (CꢂN), 1739 (lactone
CꢀO) cm−1; MS (EI) m/z (%): 311 (45) M+. Anal.
calcd for C19H21NO3 (311.38): C, 73.29; H, 6.80; N,
4.50. Found: C, 73.29; H, 7.10; N, 4.34%.
(b) A solution of p-toluenesulfonyl chloride (575 mg,
3.02 mmol) in abs. pyridine (2.5 ml) was added drop-
wise to a solution of 2 (575 mg, 1.84 mmol) in abs.
pyridine (5.5 ml) at 60°C. After 36 h, the reaction
mixture was poured into 50 ml of diluted H2SO4. It
was extracted with CH2Cl2, the organic phase was
washed with water, dried (Na2SO4) and evaporated.
The crude product was chromatographed on silica gel
with CH2Cl2 until the less polar part 7 (53 mg, 10%)
was eluted, then with MeOH/CH2Cl2 (1:9) to obtain
5 (429 mg, 74%). The resulted compound 5 was iden-
tical with the product of the Jones oxidation of 4 (see
above).
4.5. 3-Methoxy-17b-hydroxy-estra-1,3,5(10)-trien-16-one
8
Compound 2 (223 mg, 0.7 mmol) was dissolved in
ethanol (30 ml) under argon. Ethanol/hydrochloric
acid (1:1, 6 ml), and aq. TiCl3 (15%, 2.8 ml, 3.1 mmol)
was added. The violet solution became a white slurry.
It was first stirred for 8 h at rt and then refluxed for
10 h. The mixture was poured onto water (100 ml),
extracted three times with CH2Cl2, dried (Na2SO4) and
evaporated. The residue (194 mg) was chro-
matographed on silica gel with t-butyl methyl ether/
CH2Cl2 (1:9) yielding 8 (145 mg, 68%) as a white
solid. Mp 168–169°C [169.5–171°C, lit.28]; [a]D20=−134
(c 1, CHCl3) [−88, ethanol. lit.28]; IR (ATR): 3420
(OH), 2935, 2867, 1734 (CꢀO), 1499, 1040 cm−1; MS
(ESI) m/z (%):355 (100) [M+Na+MeOH]+, 323 (80)
[M+Na]+, 15 [M+H]+; HRMS m/z: found 323.16150
[M+Na]+, calcd: 323.16231 for C19H24NaO3.
3-Methoxy-16,17-secoestra-1,3,5(10)-trien-16-nitrile-17-
oic acid anhydride 7
Mp 175–177°C (CH2Cl2/n-hexane): [a]2D0=+77 (c 1,
1
CHCl3); H NMR (CDCl3, 500 MHz): d 1.36 (s, 6H,
2×18-H3), 2.92 (m, 4H, 2×6-H2), 3.77 (s, 6H, 2×

2712
A. Magyar et al. / Tetrahedron: Asymmetry 14 (2003) 2705–2715
4.6. 13a-Isocyanato-3-methoxy-16,17-seco-17-nor-estra-
10 (937 mg, 93%). Mp 97–99°C (CH2Cl2/heptane);
[a]2D0=+94 (c 1, CHCl3); 1H NMR: d 1.04 (s, 3H,
18-H3), 2.68 (A part of an ABX-system, dd, J=17.4,
4.6 Hz, 1H, 15-H), 2.79 (B part of an ABX-system, dd,
J=17.4, 4.9 Hz, 1H, 15-H%), 2.90 (m, 2H, 6-H2), 3.76 (s,
3H, OMe), 5.95 (br s, 1H, N-H), 6.62 (d, J=2.8 Hz,
1H, 4-H), 6.70 (dd, J=8.6, 2.8 Hz, 1H, 2-H), 7.17 (d,
J=8.6 Hz, 1H, 1-H) ppm; 13C NMR: d 15.2 (C-15),
20.78 (C-18), 27.4 (C-7), 28.1 (C-11), 30.0 (C-6), 41.3
(C-8), 42.9 (C-9), 45.4 (C-12), 49.3 (C-14), 51.9 (C-13),
55.2 (3-OMe), 111.9 (C-2), 113.4 (C-4), 120.3 (C-16,
CꢂN), 126.4 (C-1), 131.4 (C-10), 137.5 (C-5), 157.7
(C-3), ppm; IR (ATR): 3353 (N-H), 2242 (-CꢂN) cm−1.
MS (ESI) m/z (%): 307 (15) [M+Na]+, 285 (100) [M+
H]+, 268 (24). HRMS m/z: found 285.19532 [M+H]+,
calcd: 285.19669 for C18H25N2O.
1,3,5(10)-trien-16-nitrile 9
Compound 5 (0.63 g, 2.00 mmol), diphenylphosphoryl
azide (0.6 ml, 2.8 mmol) and triethylamine (0.4 ml, 2.86
mmol) in abs. toluene (50 ml) were refluxed for 3.5 h.
The mixture was diluted with toluene, washed with aq.
K2CO3, dried (MgSO4) and filtered through silica gel.
The solvent was evaporated yielding the crude product
(0.83 g). Crystallization from diethyl ether yields 9 (465
mg, 75%) as a white solid. Mp 92–95°C (Et2O); [a]2D0=
1
+246 (c 1, CHCl3); H NMR (400 MHz, CDCl3): d 1.38
(s, 3H, 18-H3), 2.59 (A part of an ABX-system, dd,
J=17.4, 4.0 Hz, 1H, 15-H), 2.69 (B part of an ABX-
system, dd, J=17.4, 5.3 Hz, 1H, 15-H%), 2.91 (m, 2H,
6-H2), 3.76 (s, 3H, OMe), 6.63 (d, J=2.8 Hz, 2H, 4-H),
6.71 (dd, J=8.7, 2.8 Hz, 2H, 2-H), 7.15 (d, J=8.7 Hz,
2H, 1-H) ppm; 13C NMR (CDCl3, 125 MHz): d 16.4
(C-15), 21.9 (C-18), 55.2 (3-OMe), 61.7 (C-13), 112.0
(C-2), 113.5 (C-4), 118.7 (C-16, CꢂN), 123.8 (NCO),
126.3 (C-1), 130.5 (C-10), 137.2 (C-5), 157.9 (C-3) ppm;
IR (ATR): 2240 (-CꢂN), 2170 (-NCO) cm−1; MS (ESI)
m/z (%): 365 (60) [M+Na+MeOH]+, 333 (100) [M+Na]+;
HRMS m/z: found 333.15773 [M+Na]+, calcd:
333.15790 for C19H22NaN2O2. Anal. calcd for
C19H22N2O2 (310.40): C, 73.52; H, 7.14; N, 9.02.
Found: C, 74.16; H, 7.32; N, 9.06%.
4.9. 3-Methoxy-13a-N[(2-pyridyl)methylene]amino-
16,17-seco-17-nor-estra-1,3,5(10)-trien-16-nitrile 12
Amine 11 (284 mg, 1.0 mmol) and pyridine-2-carbalde-
hyde (0.1 ml, 1.0 mmol) was refluxed in abs. methanol
(10 ml) for 24 h. The solvent was evaporated yielding
12 as an oil (373 mg, 100%). The substance was subse-
quently used without further purification. [a]2D0=+157 (c
1, CHCl3); 1H NMR: d 1.29 (s, 3H, 18-H3), 2.57 (A part
of an ABX-system, dd, J=17.4, 4.2 Hz, 1H, 15-H), 2.68
(B part of an ABX-system, dd, J=17.4, 5.4 Hz, 1H,
15-H%), 2.94 (m, 2H, 6-H2), 3.77 (s, 3H, OMe), 6.62 (d,
J=2.7 Hz, 1H, 4-H), 6.72 (dd, J=8.6, 2.7 Hz, 1H,
2-H), 7.21 (d, J=8.6 Hz, 1H, 1-H), 7.32 (ddd, J=7.5,
4.8, 1.2 Hz, 1H, 5-HPy), 7.75 (ddd, J=7.9, 7.5, 1.7 Hz,
1H, 4-HPy), 8.04 (ddd, J=7.9, 7.5, 1.7 Hz, 1H, 3-HPy),
4.7. 13a-(N-Methoxycarbonyl)amido-3-methoxy-16,17-
seco-17-nor-estra-1,3,5(10)-trien-16-nitrile 10
Isocyanate 9 (310 mg, 1.0 mmol) was stirred in 5%
KOH/MeOH (20 ml) for 20 min. After addition of
water (50 ml), the mixture was extracted three times
with ether. The combined organic phases were washed
with aq. NaCl solution, dried (Na2SO4) and evaporated
under vacuo. The product (340 mg, 99%) was crystal-
lized from Et2O yielding 10 (308 mg, 90%). Mp 81–
84°C (Et2O); [a]D20=+169 (c 1, CHCl3); 1H NMR: d 1.23
(s, 3H, 18-H3), 2.89 (m, 2H, 6-H2), 3.61 (s, 3H,
NHCOOMe), 3.76 (s, 3H, OMe), 4.68 (br s, 1H, N-H),
6.62 (d, J=2.8 Hz, 1H, 4-H), 6.70 (dd, J=8.6, 2.8 Hz,
1H, 2-H), 7.17 (d, J=8.6 Hz, 1H, 1-H) ppm; 13C NMR:
d 15.5 (C-16), 20.6 (C-18), 55.2 (3-OMe), 56.6 (C-13),
111.9 (C-2), 113.4 (C-4), 119.3 (C-16, CꢂN), 126.4
8.45 (s, 1H, NꢀCH6 -Py), 8.63 (ddd, J=4.8, 1.7, 0.9 Hz,
1H, 6-HPy) ppm; 13C NMR: d 15.9 (C-15), 18.6 (C-18),
55.2 (3-OMe), 62.2 (C-13), 111.9 (C-2), 113.5 (C-4),
120.0 (CꢂN), 120.9 (CPy), 124.8 (CPy), 126.4 (C-1), 131.4
(C-10), 136.6 (CPy), 137.5 (C-5), 149.4 (CPy-6), 155.1
(CPy-2), 157.8 (C-3), 158.6 (NꢀC6 H) ppm; IR (ATR):
2242 (CꢂN) cm−1; MS (ESI) m/z (%): 412 (8) [M+K]+
396 (100) [M+Na]+, 374 (10) [M+H]+; HRMS m/z:
found 396.20515 [M+Na]+, calcd: 396.20518 for
C24H27NaN3O.
4.10. 3-Methoxy-13a-N[(2-pyridyl)methyl]amino-16,17-
seco-17-nor-estra-1,3,5(10)-trien-16-nitrile 13
(C-1), 131.3 (C-10), 137.4 (C-5), 154.9 (NHC6 O), 157.7
(C-3) ppm; IR (ATR): 2246 (CꢂN), 1635 (CꢀO) cm−1;
MS (ESI) m/z (%): 381 (42) [M+K]+, 365 (100) [M+
Na]+; HRMS m/z: found 365.18349 [M+Na]+, calcd:
365.18411 for C20H26N2O3Na. Anal. calcd for
C20H26N2O3 (342.44): C, 70.15; H, 7.65; N, 8.18.
Found: C, 70.97; H, 8.29; N, 8.82%.
To a solution of the imine 12 (373 mg, 1.0 mmol) in
methanol (10 ml), NaBH4 (373 mg, 9.9 mmol) was
added in small portions at 0°C. After 10 min, the
reaction mixture was treated with water. The white
precipitate was filtered to yield 360 mg (96%) of the
sec-amine 16 as a glassy product. Mp 45–47°C, [a]2D0=
1
4.8. 13a-Amino-3-methoxy-16,17-seco-17-nor-estra-
1,3,5(10)-trien-16-nitrile 11
+59 (c 1, CHCl3); H NMR: d 1.09 (s, 3H, 18-H3), 2.70
(dd, J=17.1, 4.3 Hz, 1-H, 15-H), 2.80–3.00 (m, 3H,
6-H2 and 15-H%), 3.76 (s, 3H, OMe), 6.63 (d, J=2.7 Hz,
2H, 4-H), 6.71 (dd, J=8.6, 2.7 Hz, 1H, 2-H), 7.16 (m,
2H, 1-H and 5-HPy), 7.33 (d, J=7.9 Hz, 1H, 3-HPy),
7.64 (td, J=7.9, 1.8 Hz, 1H, 4-HPy), 8.53 (m, 1H,
6-HPy) ppm; 13C NMR: d 14.9 (C-15), 19.7 (C-18), 55.2
(3-OMe), 55.4 (C-13), 111.9 (C-2), 113.5 (C-4), 120.5
(C-16, CꢂN), 121.9 and 122.3 (CPy-3 and -5), 126.4
(C-1), 131.5 (C-10), 136.5 (CPy-4), 137.5 (C-5), 149.1
To the isocyanate 9 (1.1 g, 3.5 mmol), conc. HBr (9.0
ml) was added cautiously. After gas evolution, the clear
solution was treated with 10% aq. NaOH to pH 9. The
mixture was extracted with ether and the combined
organic phases was washed with aq. NaCl, dried
(Na2SO4) and evaporated. The crude glassy product
(975 mg, 98%) was crystallized from Et2O to yield pure

A. Magyar et al. / Tetrahedron: Asymmetry 14 (2003) 2705–2715
2713
(CPy-6), 157.8 (C-3), 160.2 (CPy-2) ppm; IR (ATR):
2927, 2240 (CꢂN), 1610, 1500, 1237, 754 cm−1; MS
(ESI) m/z (%): 398 (48) [M+Na]+, 376 (100) [M+H]+;
HRMS m/z: found 376.23878 [M+H]+, calcd:
376.23889 (C24H30N3O). Anal. calcd for C24H29N3O
(375.52): C, 76.77; H, 7.78; N, 11.19. Found: C, 76.25;
H, 7.80; N, 10.80%.
precipitate was filtered (380 mg) and recrystallized from
ether to yield the sec-amine 16 (222 mg, 57%). Mp
174–177°C (ether), [a]2D0=+39 (c 1, CHCl3); 1H NMR: d
0.91 (s, 3H, 18-H3), 2.37–2.64 (m, 4H, 15-H2 and
17-H2), 2.88 (m, 2H, 6-H2), 3.76 (s, 3H, OMe), 3.89
(AB part, 2H, N-CH6 2-Py), 6.61 (d, J=2.7 Hz, 1H,
4-H), 6.70 (dd, J=8.6, 2.7 Hz, 1H, 2-H), 7.16 (m, 2H,
1-H and 5-HPy), 7.30 (d, J=7.8 Hz, 1H, 3-HPy), 7.64
(td, J=7.8, 1.8 Hz, 1H, 4-HPy), 8.55 (d, J=4.9 Hz, 1H,
6-HPy) ppm; 13C NMR: d 15.6 (C-15), 17.9 (C-18), 30.0
4.11. Bis-hydrochloride of 13: 14
A solution of the amine 13 (96 mg, 0.26 mmol), 10 ml
of ether and 1 ml of CH3OH) was saturated with HCl
gas at 0°C. The resulting bis-hydrochloride 14 crystals
were filtered, washed with cold ether and dried. Yield of
14: 104 mg (99%). Mp 174–175°C, [a]2D0=+45 (c 1,
(C-6), 37.8 (C-13), 55.2 (3-OMe), 56.0 (N-C6 H2-Py), 60.1
(17-C), 111.8 (C-2), 113.4 (C-4), 120.0 (C-16, CꢂN),
122.0 (CPy-5), 122.3 (CPy-3), 126.3 (C-1), 131.9 (C-10),
136.4 (CPy-4), 137.5 (C-5), 149.3 (CPy-6), 157.7 (C-3),
159.9 (CPy-2) ppm; IR (ATR): 2914, 2241 (CꢂN), 1609,
1500, 758 cm−1; MS (ESI) m/z (%): 412 (48) [M+Na]+,
390 (100) [M+H]+; HRMS m/z: found 390.25565 [M+
H]+, calcd: 390.25454 for C25H32N3O. Anal. calcd for
C25H31N3O (389.55): C, 77.08; H, 8.02; N, 10.79.
Found: C, 76.53; H, 7.96; N, 10.79%.
1
CHCl3); H NMR (250 MHz, DMSO): d 1.10 (s, 3H,
18-H3), 2.87 (m, 3H), 3.68 (s, 3H, OMe), 4.98 (AB part,
2H, N-CH6 2-Py), 6.66 (m, 2H), 7.06 (m, 1H), 7.53 (m,
2H), 7.95 (m, 2H), 8.65 (d, J=5.2, 1H), 9.49 (br s, 1H),
9.98 (br s, 1H) ppm; 13C NMR: d 15.4 (C-18), 54.5
(3-OMe), 69.3 (C-13), 111.2 (C-2), 113.1 (C-4), 125.6
(C-1), 143.5 (CPy-4), 154.2 (CPy-6), 157.2 (C-3), 169.3
(CPy-2) ppm; IR (ATR): 2916, 2620, 2338, 1615, 1500,
1236, 771 cm−1; MS (ESI) m/z (%): 376 (100) [M−
2HCl+H]+; HRMS m/z: found 376.23892 [M−2HCl+
H]+, calcd: 376.23889 (C24H30N3O). Anal. calcd for
C24H31N3OCl2 (448.44): C, 64.28; H, 6.97; N, 9.37.
Found: C, 63.77; H, 7.03; N, 8.97%.
4.14. 3-Methoxy-17-N(2-pyridyl)amino-16,17-secoestra-
1,3,5(10)-trien-16-nitrile 18
Aldehyde 4 (297 mg, 1.0 mmol) and 2-aminopyridine
(94 mg, 1.0 mmol) were dissolved in dichloromethane
(5 ml) under argon and 1 drop of Et2O·BF3 was added
at 0°C. The solution became dull. It was then heated to
50°C for 1 h. To the cold slurry, methanol (5.0 ml) and
NaBH4 (297 mg, 7.9 mmol) were added in small por-
tions at 0°C and stirred for 1 h. Water was added to the
mixture, which was extracted three times with ether,
washed with NaCl and dried (Na2SO4) to afford 18
(369 mg, 98%) as a pale yellow oil. It was purified
through HCl salt forming. 18 was dissolved in ether (20
ml) and treated with HCl gas. The solvent was decanted
from the sticky precipitate. The precipitate was dis-
solved in methanol and treated with 10% NaOH,
diluted with water, extracted with ether and dried
(Na2SO4) to afford pure 18 (233 mg, 62%) as an oil.
[a]2D0=+27 (c 1, CHCl3); 1H NMR: d 0.90 (s, 3H,
18-H3), 2.50 (dd, J=17.7, 3.7 Hz, 1-H, 15-H), 2.62 (dd,
J=17.7, 5.5 Hz, 1-H, 15-H%), 2.89 (m, 2H, 6-H2), 3.34
(d, J=11.2 Hz, 1H, 17-H), 3.54 (d, J=11.2 Hz, 1H,
17-H%), 3.76 (s, 3H, OMe), 4.43 (br s, 1H, NH), 6.47 (d,
J=8.3 Hz, 1H, 3-HPy), 6.62 (m, 2H, 4-H and 5-HPy),
6.70 (dd, J=8.6, 2.7 Hz, 1H, 2-H), 7.19 (d, J=8.6 Hz,
1H, 1-H), 7.40 (m, 1H, 4-HPy), 8.03 (m, 1H, 6-HPy)
ppm; 13C NMR: d 15.5 (C-15), 16.1 (C-18), 55.2 (3-
OMe), 71.0 (C-17), 108.7 and 111.8 and 113.3 and 114.0
(C-4 and -2 and CPy-3 and -5), 120.0 (C-16, CꢂN),
126.4 (C-1), 131.8 (C-10), 137.5 and 137.8 (C-5 and
CPy-4), 147.9 (CPy-6), 157.6 (C-3), 158.3 (CPy-2) ppm;
IR (ATR): 2915, 2243 (CꢂN), 1607, 1500, 1043, 773
cm−1; MS (ESI) m/z (%): 398 (100) [M+Na]+, 376 (10)
[M+H]+; HRMS m/z: found 376.23963 [M+H]+, calcd:
376.23889 (C24H30N3O).
4.12. (17E)-3-Methoxy-17-N[(2-pyridyl)methyl]imino-
16,17-secoestra-1,3,5(10)-trien-16-nitrile 15
Aldehyde
4
(1.49 g, 5.00 mmol) and 2-
(aminomethyl)pyridine (0.5 ml, 5.0 mmol) were refluxed
in methanol (100 ml) and THF (30 ml) for 2 h. After
stirring overnight at rt, the solvents were removed and
the product 15 was crystallized from ethanol (1.57 g,
81%). Mp 102–104°C (methanol); [a]2D0=+62 (c 1,
CHCl3); 1H NMR: d 1.18 (s, 3H, 18-H3), 2.57 (dd,
J=17.6, 5.0 Hz, 1H, 15-H), 2.90 (m, 2H, 6-H2), 3.76 (s,
3H, OMe), 4.73 (AB part, 2H, N-CH6 2-Py), 6.63 (d,
J=2.7 Hz, 1H, 4-H), 6.71 (dd, J=8.6, 2.7 Hz, 1H,
2-H), 7.18 (m, 2H, 1-H and 5-Hpy), 7.35 (d, J=7.9 Hz,
1H, 3-Hpy), 7.66 (m, 2H, 4-Hpy and -H
1H, 6-Hpy) ppm; 13C NMR: d 16.0 (C-18), 17.2 (C-15),
29.9 (C-6), 43.6 (C-13), 55.2 (3-OMe), 66.5 (N-CH2-Py),
6 CꢀN-), 8.55 (m,
6
112.0 (C-2), 113.5 (C-4), 119.9 (C-16, CꢂN), 126.4
(C-1), 131.4 (C-10), 136.7 (CPy-4), 137.5 (C-5), 149.3
(CPy-6), 157.8 (CPy-2), 158.8 (C-3), 173.3 (C-17, -CꢀN-)
ppm; IR (ATR): 2235 (CꢂN) cm−1; MS (ESI) m/z (%):
410 (100) [M+Na]+, 388 (15) [M+H]+; HRMS m/z:
found 388.23961 [M+H]+, calcd: 388.23888 for
C25H30N3O. Anal. calcd for C25H29N3O (387.53): C,
77.50; H, 7.54; N, 10.84. Found: C, 77.63; H, 7.15; N,
10.42%.
4.13. 3-Methoxy-17-N[(2-pyridyl)methyl]amino-16,17-
secoestra-1,3,5(10)-trien-16-nitrile 16
4.15. Copper complexation and O2 activation with 15
To a solution of the imine 15 (388 mg, 1.0 mmol) in
methanol (10 ml), NaBH4 (388 mg, 10.3 mmol) was
added in small portions at 0°C. After 10 min, the
reaction mixture was treated with water. The white
The steroid ligand 15 (775 mg, 2.0 mmol) was dissolved
in abs. CH2Cl2 (100 ml) under argon. The solution was
degassed 3 times and CuI(CH3CN)4PF6 (745 mg, 2

2714
A. Magyar et al. / Tetrahedron: Asymmetry 14 (2003) 2705–2715
mmol) was added under argon. The resulting yellow
solution was stirred for 20 h. The flask was degassed
and filled three times with pure O2. This resulted in an
oily green mixture. The mixture was kept for 3 days
under O2 and then extracted three times with conc.
NH4OH (stirred for 30 min with conc. NH4OH, the
blue aqueous phase was separated), the brown organic
phase was dried (Na2SO4) and evaporated giving an
oily product (760 mg). MS (ESI) m/z (%): 426 (12)
[15+K]+, 406 (78) [15+19]+, 388 (30) [12+H]+, 315 (100)
[4+18]+, 297 (18). HRMS: 406, C25H32N3O2 (15+H2O+
H); 315, C19H27N2O2 (4+NH3+H).
Komatsu, M.; Fukuzumi, S. J. Am. Chem. Soc. 1998,
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10. Itoh, S.; Taki, M.; Nakao, H.; Holland, P. L.; Tolman,
W. B.; Que, L., Jr.; Fukuzumi, S. Angew. Chem. 2000,
112, 409–411; Angew. Chem., Int. Ed. 2000, 39, 398–
400.
11. Blain, I.; Giorgi, M.; DeRiggi, I.; Reglier, M. Eur. J.
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12. Blain, I.; Giorgi, M.; DeRiggi, I.; Re´glier, M. Eur. J.
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13. Gonschior, M.; Ko¨tteritzsch, M.; Rost, M.; Scho¨necker,
B.; Wyrwa, R. Tetrahedron: Asymmetry 2000, 11, 2159–
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14. Scho¨necker, B.; Zheldakova, T.; Liu, Y.; Ko¨tteritzsch,
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3361–3365; Angew. Chem., Int Ed. 2003, 42, 3240–3244.
15. Magyar, A.; Scho¨necker, B.; Wo¨lfling, J.; Schneider,
G.; Gu¨nther, W.; Go¨rls, H. Tetrahedron: Asymmetry
2003, 14, 1925–1934.
The resulting mixture was chromatographed on silica
gel with CH2Cl2, MeOH/CH2Cl2 (1:9) and NH4OH/
MeOH (5:95) yielding 4 (72 mg, 12%), 15 (256 mg,
34%) and a fraction (150 mg) of a nonseparable
mixture.
16. Miljkovic´, D.; Petrovic´, J. J. Org. Chem. 1977, 42,
2101–2102.
4.16. Copper complexation and O2 activation with 12
17. Miljkovic´, D.; Petrovic´, J.; Hadzic, P. Tetrahedron
1978, 34, 3575–3577.
The steroid ligand 12 (187 mg, 0.5 mmol) was dissolved
in abs. CH2Cl2 (28 ml) under argon. Reaction with
Cu1(CH3CN)4PF6 (186 mg, 0.5 mmol), O2 and conc.
NH4OH as described for 15 (4.15.) gave an oily product
(154 mg). MS (ESI) m/z (%): 396 (100) [12+Na]+, 374
(80) [12+H]+, 295 (58) [11+H]+. Preparative TLC with
t-butyl methyl ether/CH2Cl2 (1:9) gave 12 (105 mg,
56%).
18. Litvan, F.; Robinson, R. J. Chem. Soc. 1938, 1997–
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We gratefully acknowledge financial support from the
Deutsche Forschungsgemeinschaft (Sonderforschungs-
bereich 436), the Thuringian Ministerium fu¨r Wis-
senschaft, Forschung und Kunst, the Fonds der
Chemischen Industrie and Schering AG for the gift of
steroids.
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