Intramolecular γ-hydroxylations of nonactivated C-H bonds with copper complexes and molecular oxygen

Article abstract of DOI:10.1002/chem.200306054

Copper(I) complexes incorporating the isomeric bidentate ligands IMPY (iminomethyl-2-pyridines) or AMPY (aminomethylene-2-pyridines) are quite unusual in their ability to bind and activate molecular oxygen. Using these complexes, hydroxylations of nonactivated CH, CH₂, or CH₃ groups in the γ-position in relation to the imino-nitrogen atom, and with a specific orientation of one H atom with respect to the binuclear Cu-O species, can be achieved in synthetically useful yields. Through mechanistic studies employing conformationally well-defined molecules (for example, cyclic isoprenoids), coupled with solid-state X-ray structure analyses and force-field calculations, we postulate a seven-membered transition state for this reaction in which six atoms lie approximately in a plane. This plane is defined by the positions of the lone pairs on the nitrogen atoms, as well as the copper and the oxygen atoms. For a successful hydroxylation, one hydrogen atom should be located close to this plane. Prediction of the stereochemical course of these reactions is possible based on a simple geometrical criterion. The convenient introduction of IMPY and AMPY groups as auxiliaries into oxo and primary amino compounds and the simple hydrolysis after the hydroxylation procedure has allowed the synthesis of 3-hydroxy-1-oxo and 3-hydroxy-1-amino compounds. If desired, the 3-hydroxy-1-IMPY and -1-AMPY compounds can be reduced with NaBH4 to obtain 3-hydroxy-1-aminomethylpyridines. For a successful hydroxylation procedure, the method employed for the synthesis of the Cu^I complexes is very important. Starting either from Cu^I salts or from Cu^II salts with a subsequent reduction with benzoin/triethylamine may turn out to be the better way, depending on the ligand and the molecular structure.

Full text of DOI:10.1002/chem.200306054

FULL PAPER
À
Intramolecular g-Hydroxylations of Nonactivated C H Bonds with Copper
Complexes and Molecular Oxygen
[
a]
[b]
[a]
[a]
Bruno Schçnecker,* Tatjana Zheldakova, Corinna Lange, Wolfgang Günther,
[
c]
[d]
Helmar Gçrls, and Martin Bohl
Abstract: Copper(i) complexes incor-
porating the isomeric bidentate ligands
IMPY (iminomethyl-2-pyridines) or
AMPY (aminomethylene-2-pyridines)
are quite unusual in their ability to
bind and activate molecular oxygen.
Using these complexes, hydroxylations
calculations, we postulate
a
seven-
IMPY and AMPY groups as auxiliaries
into oxo and primary amino com-
pounds and the simple hydrolysis after
the hydroxylation procedure has al-
lowed the synthesis of 3-hydroxy-1-oxo
and 3-hydroxy-1-amino compounds. If
desired, the 3-hydroxy-1-IMPY and -1-
AMPY compounds can be reduced
membered transition state for this reac-
tion in which six atoms lie approxi-
mately in a plane. This plane is defined
by the positions of the lone pairs on
the nitrogen atoms, as well as the
copper and the oxygen atoms. For a
successful hydroxylation, one hydrogen
atom should be located close to this
plane. Prediction of the stereochemical
course of these reactions is possible
based on a simple geometrical criteri-
on. The convenient introduction of
of nonactivated CH, CH , or CH3
2
groups in the g-position in relation to
the imino-nitrogen atom, and with a
specific orientation of one H atom with
respect to the binuclear CuÀO species,
with NaBH to obtain 3-hydroxy-1-ami-
4
nomethylpyridines. For a successful hy-
droxylation procedure, the method em-
I
ployed for the synthesis of the Cu
can be achieved in synthetically useful
yields. Through mechanistic studies
employing conformationally well-de-
fined molecules (for example, cyclic
isoprenoids), coupled with solid-state
X-ray structure analyses and force-field
complexes is very important. Starting
I
II
either from Cu salts or from Cu salts
with a subsequent reduction with ben-
zoin/triethylamine may turn out to be
the better way, depending on the
ligand and the molecular structure.
Keywords:
copper
activation · steroids
CÀH activation
·
·
hydroxylation
·
OÀO
Introduction
to investigate such reactions employing simple biomimetic
copper complexes. Quite some success has been achieved in
the past in activating molecular oxygen, the investigation
[2]
The ability of copper-containing enzymes to regio- and ster-
eoselectively hydroxylate substrates with molecular
oxygen has inspired bioinorganic and bioorganic chemists
[
3]
of oxidizing species, and in the hydroxylation of aromatic
[
1]
[4]
and benzylic CÀH bonds of ligands. It seems to be much
more difficult to hydroxylate nonactivated CÀH bonds. The
[
5]
work of Thompson (N,N,N’,N’-tetraethyl ethylenediamine )
and Reglier and co-workers {N,N-bis[2-(2-pyridyl)ethyl]ami-
[
a] Prof. Dr. B. Schçnecker, Dr. C. Lange, Dr. W. Günther
Institut für Organische Chemie und Makromolekulare Chemie der
Friedrich-Schiller-Universität Jena
Humboldtstrasse 10, 07743 Jena (Germany)
Fax : (+49)364-194-8292
[6]
[6]
nopropane and -cyclopentane }, our own work {17b-N-[2-
(2-pyridyl)ethyl]amino-, 17b-(2-pyridylmethyl)amino ste-
[7]
[8]
roids, and a 17a-aza-N-[2-(2-pyridyl)ethyl]amino steroid },
and work by Masuda et al. [cis,cis-1,3,5-tris(isobutylamino)-
E-mail: c8scbr@uni-jena.de
[
b] Dr. T. Zheldakova
[9]
cyclohexane ] is summarized in Figure 1.
Institute of Bioorganic Chemistry of the National Academy of
Sciences of Belarus, Minsk (Belarus)
Using conformationally more restricted bidentate ligands
incorporating an iminomethyl- or iminoethyl-2-pyridine
moiety at the 17-position of a steroid molecule, we have ob-
served for the first time a regio- and stereospecific g-
[
c] Dr. H. Gçrls
Institut für Anorganische und Analytische Chemie der Friedrich-
Schiller-Universität Jena
Lessingstrasse 8, 07743 Jena (Germany)
hydroxylation of a nonactivated CH group.
2
[
d] Dr. M. Bohl
1
2b-Hydroxylated steroids could be obtained in practical-
Tripos GmbH, Martin-Kollar-Str. 17, 81829 München (Germany)
and
Institut für Molekulare Biotechnologie, Beutenbergstrasse 11
ly useful yields of 40 to 50%. After the hydroxylation proce-
dure (Scheme 1), hydrolysis or reduction of the imino bond
was possible, giving the 12b-hydroxy-17-ketone or 12b-hy-
0
7745 Jena (Germany)
Chem. Eur. J. 2004, 10, 6029 – 6042
DOI: 10.1002/chem.200306054
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6029

FULL PAPER
Figure 1. b-Hydroxylation of nonactivated CÀH bonds.
Abstract in German: Kupfer(i)komplexe von zwei Typen iso-
merer zweizähniger Liganden (IMPY: Iminomethyl-2-pyri-
dine, AMPY: Aminomethylen-2-pyridine) binden und akti-
vieren molekularen Sauerstoff. Nichtaktivierte CH-, CH2-
oder CH -Gruppen in g-Stellung zum Iminstickstoff, deren
3
H-Atome in die Ebene der Zweikern-Cu-O-Species gelangen
kçnnen, werden in praktisch verwertbaren Ausbeuten hy-
droxyliert. An Beispielen konformativ gut definierter Mole-
küle (cyclische Isoprenoide), Rçntgenkristallstrukturanalysen
und Kraftfeldberechnungen kann ein siebengliedriger Über-
gangszustand mit sechs Atomen in nahezu einer Ebene vor-
geschlagen werden. Die Ebene ist determiniert durch die
freien Elektronenpaare der N-Atome und die Kupfer- und
Sauerstoffatome. Vorraussetzung für eine erfolgreiche Hy-
droxylierung ist, daß ein H-Atom in diese Ebene gelangt. Für
eine Voraussage des stereochemischen Verlaufs wird eine einf-
ache geometrische Maßzahl verwendet. Durch die einfache
Einführung der IMPY- oder AMPY-Gruppe als Auxiliare in
Oxo- bzw. primäre Amino-Verbindungen und die leichte Hy-
drolyse nach der Hydroxylierung sind auf kurzem Wege und
bequem 3-Hydroxy-1-oxo- und 3-Hydroxy-1-amino-Verbin-
dungen zugänglich. Falls gewünscht kçnnen jedoch auch die
als Primärprodukte entstehenden 3-Hydroxy-1-IMPY- und 3-
Hydroxy-1-AMPY-Verbindungen mit NaBH zu 3-Hydroxy-
4
1-aminomethyl-pyridinen reduziert werden. Für eine erfol-
greiche Hydroxylierung ist die Methode zur Herstellung der
I
Cu -Komplexe sehr bedeutsam. In Abhängigkeit von Ligan-
2
Scheme 1. g-Hydroxylation of a nonactivated CH group.
I
den- und Molekülstruktur ist entweder der Start mit Cu -
Salzen oder der mit Cu -Salzen und nachfolgender Reduk-
tion mit Benzoin/Triethylamin der bessere Weg für die fol-
gende Hydroxylierung mit molekularem Sauerstoff.
II
[7]
droxy-17b-sec-amine, respectively. For somewhat higher
yields, the iminomethylpyridine group (IMPY ligands)
proved preferable.
6030
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 6029 – 6042

Intramolecular g-Hydroxylations in Copper Complexes
6029 – 6042
We have presented an initial stereochemical model for H-
abstraction from the dinuclear copper–oxygen complex of 1,
which consists of a seven-membered ring with six atoms
lying nearly in a plane (Figure 2).
with other IMPY derivatives. To find further suitable li-
gands, we have investigated isomeric ligands containing an
aminomethylene pyridine structure (AMPY ligands) in
which the C=N double bond is conjugated with the pyridine
[10,11]
ring.
Finally, we have calcu-
lated the conformation of the li-
gands in the lowest energy state
and the conformation of the
IMPY and AMPY steroids
most appropriate to form the
copper–oxygen complex. On
the basis of these results, we
have modeled the copper–
oxygen complexes. We suggest
a mechanism similar to that de-
scribed, and recently also sup-
ported by calculations, for the
b-hydroxylation of benzylic
CH groups with 2-[(2-pyridyl)-
2
[
4f]
ethyl]amino ligands.
Initially
2
2
generated (m-h :h -peroxo)di-
copper(ii) complexes from cop-
per(i) complexes and molecular
oxygen are in equilibrium with
bis(m-oxo)dicopper(iii)
com-
plexes. These should be the spe-
cies that are able to attack the
CÀH bond with subsequent cre-
ation of
Figure 2).
a
CÀO bond (see
Results and Discussion
Hydroxylations with IMPY li-
gands: Two methods can be
successfully applied for the b-
hydroxylation
of
benzylic
groups in the b-position to the
central nitrogen of 2-[(2-
pyridyl)ethyl]amino
ligands.
Only 50% of the ligand in the
dinuclear complex can be hy-
droxylated when one starts with
copper(i) salts for complexation
with subsequent addition of
molecular oxygen (method A).
To
achieve
quantitative
hydroxyllation, Fukuzumi and
co-workers started with cop-
per(ii) complexes, which were
then reduced with benzoin and
Figure 2. a) Model for the copper–oxygen complex of the 13b-configured IMPY steroid 1 in a conformation triethylamine to copper(i) com-
forming a seven-membered ring (six atoms N1, Cu1, O1, 12b-H, C13, C17 in a plane; C12out of this plane)
and b) possible mechanism for g-hydroxylation.
plexes (method B). After addi-
tion of molecular oxygen and
completion of hydroxylation
We assume that the orientation of the H atom in this
plane is a requirement for a successful hydroxylation proce-
dure. To support this hypothesis, we now report reactions
turnover, an excess of benzoin/triethylamine was used to
reduce the copper(ii) complex to the copper(i) complex.
This could then react with oxygen once more for further hy-
Chem. Eur. J. 2004, 10, 6029 – 6042
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6031

B. Schçnecker et al.
FULL PAPER
[4b,c,d]
droxylation of the ligand.
Interestingly enough, Reglier
and co-workers were only able to hydroxylate nonactivated
[6]
CH groups by way of method B. We also successfully em-
2
ployed method B for b- and g-hydroxylations of nonactivat-
[7]
ed CH groups of bidentate ligands. Very recently, howev-
2
er, two examples of b-hydroxylation of nonactivated CÀH
[8,9]
bonds using method A have been described.
We were
able to show that 17-IMPY-3-methoxy-estra-1,3,5(10)-triene
1, Scheme 1) can be stereo- and regioselectively hydroxylat-
ed in the 12b-position (g-hydroxylation) in nearly 50% yield
(
[7]
using method B. To investigate the stereochemical implica-
tions of this interesting reaction employing IMPY ligands,
we describe herein two new 17-IMPY steroidal ligands 3
and 6 (Scheme 2) and the IMPY derivative of (R)-camphor
Scheme 3. Hydroxylation of IMPY-(1R)-camphor. a) PyCH
ing xylene, p-toluenesulfonic acid; b) 1. Cu(CH CN) PF , acetone, Ar; 2.
; c) 1. Cu(CF SO , acetone; 2. benzoin, N(C , Ar; 3. O ; d) 1.
NH OH O; 2. chromatography on silica gel; e) 1. acetic acid, MeOH,
08C; 2. chromatography on silica gel.
2 2
NH , reflux-
3
4
6
O
2
3
3
)
2
2
H
5
)
3
2
4
, 2
H
9
12 (Scheme 3).
Hydroxylation of the d-homo-17a-IMPY steroid 3: Com-
pounds 2 and 3 (Scheme 2) have a trans-perhydro-naphtha-
lene system instead of the trans-perhydro-indane system of
the IMPY compound 1 (Scheme 1); 3 is quite sensitive to
hydrolysis.
À1
the same energy (within 0.01 kcalmol ) are calculated (blue
and orange in Figure 3). The conformation found in the
[7]
crystal (red in Figure 4) is located in a favorable energy
region but was computed to be 1.6 kcalmol higher in
À1
As expected, a comparison of the X-ray analyses of both
IMPY ligands 1 (Scheme 1) and 3 (Scheme 2) reveals only
small geometrical differences.
For comparison between 1 and 3, the results of a confor-
mational analysis (calculated with the MMFF94 force field)
for a model of the 13b-17-IMPY-estratriene steroid 1 are
given in Figure 3. Two separated energy minima with nearly
energy. The energy maps and comparison of the different
low-energy conformations indicate that the 17-side chain is
flexible enough to adopt quite different orientations with re-
spect to the steroid skeleton. Because of the rigidity im-
posed by the C17=N1 double bond, there is only one confor-
mation (shown in Figure 2) in which the nitrogen lone pairs
are suitably predisposed to bind to the copper ion. The rela-
Scheme 2. g-Hydroxylation with IMPY ligands of the estra-1,3,5(10)-triene series. a) PyCH
Cu(CH CN) PF , acetone, Ar; 2. O ; c) 1. Cu(CF SO , acetone; 2. benzoin, N(C , Ar; 3. O
chromatography on silica gel; e) 1. Cu(CF SO )(CH ), acetone, Ar; 2. O
2
NH
2
, refluxing toluene, p-toluenesulfonic acid; b) 1.
3
4
6
2
3
3
)
2
2
H
5
)
3
2
; d) 1. NH
4
OH, H
2
O; 2. acetic acid, MeOH, 908C; 3.
3
3
3
C
6
H
5
2
.
6032
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org Chem. Eur. J. 2004, 10, 6029 – 6042

Intramolecular g-Hydroxylations in Copper Complexes
6029 – 6042
IMPY group able to bind the
copper ion (illustrated in
Figure 4 and see Figure 6).
For the energetically favored
C-ring chair steroid, the O1
oxygen is located close to the
1
2b-hydrogen (distance 0.67 Š)
and lies near to the least-
squares plane formed by the
following six atoms, with the
displacements from this plane
in Š given in parentheses: N1
(
0.05), Cu1 (0.09), O1 (0.15),
Figure 3. Conformational space of the IMPY steroid model 1 (torsional angle 1: C17=N-C-CPy; angle 2: N-C- 12b-H (0.31), C13 (0.16), C17
À1
[7]
C
(
Py-NPy) with color-coded MMFF94 energy in kcalmol (left) and superposition (right) of crystal structure
(
0.05). The distance from this
red structure related to red cross left) and two calculated energy-minimum structures (blue and orange struc-
ture corresponding to blue and orange cross, respectively).
plane to C12is 0.54 Š.
tive conformational energy required for this steroid (without
the four-membered CuÀO ring) to adopt the conformation
À1
displayed in Figure 2is 7.6 kcalmol . It is evident that only
the 12b-H can be abstracted from the O1 oxygen atom in
this conformation. The O1–12bH distance is 0.67 Š. The
least-squares plane through the following six atoms has a
root-mean-square deviation of 0.09 Š and the following in-
dividual displacements (in Š) above/below the plane: N1
(
(
0.06), Cu1 (0.09), O1 (0.02), 12b-H (0.12), C13 (0.13), C17
0.05). Note that the C12carbon atom is displaced from this
plane by 0.59 Š.
The theoretical results described above and the structural
similarity between d-homo compound 3 and compound 1
would lead us to also expect hydroxylation in the 12b-posi-
tion for the d-homo steroid 3. We employed method B with
acetone as the solvent. After hydroxylation, the reaction
mixture was decomplexed and hydrolyzed with aqueous am-
monia. We succeeded in isolating 54% of the ketone 2 and
only 11% of the expected 12b-hydroxy-17a-ketone 4. Using
method A, 39% of 2 and 18% of 4 were obtained. Despite
the possibility of hydrolysis of 3 during the hydroxylation
procedure, the higher yield with method A is remarkable
and is in contrast to the hydroxylation of 1 (method B:
Figure 4. Model for the copper–oxygen complex of the 13a-configured
IMPY steroid 6 adopting a C-ring chair conformation (approximate
plane through the atoms N1, Cu1, O1, 12b-H, C13, C17; C12out of
plane).
Although the C/D ring junction is different, the orienta-
tion of the IMPY group with respect to the equatorial 12b-
H is similar to that in the normal 13b-steroid (see Figure 2
and Figure 4). Thus, the 13a-steroid can also be expected to
undergo a successful 12b-hydroxylation.
50%, method A: 29%). These results show a considerable
sensitivity to small structural changes.
Hydroxylation of 13a-steroid 6: Another interesting exam-
ple is the 13a-17-ketone 5 (Scheme 2) which possesses, in
contrast to the natural steroids, a non-natural C/D-cis hy-
drindane system. Such non-natural steroids are also interest-
After reaction of the IMPY compound 6 according to
method B, followed by decomplexation and hydrolysis, we
succeeded in isolating (in addition to the 13a-17-ketone 5)
only a small amount of a hydroxylated product (6%). Using
method A, the yield of this product could again be raised to
34%. The structure of this product as the 12b-hydroxy com-
pound 8 was determined by spectroscopic methods and by
an X-ray structural analysis (Figure 5).
[13]
ing because of their conformation and biological activity.
Since 13a-steroids are known to adopt two different C-
ring conformations (chair and twist-boat), both of these con-
formations have been constructed and relaxed by short mo-
lecular dynamics simulations and subsequent energy minimi-
zations of representative structures. A model for the C-ring
In one experiment, we investigated the influence of the
anion of the copper(i) salt on the hydroxylation process. Re-
chair steroid 6 with the 17-IMPY side chain was found to be
acting 6 with copper(i) triflate instead of the PF salt, we
6
À1
2.8 kcalmol lower in energy than the twist-boat form. This
only isolated 19% of the expected 12b-hydroxylated com-
pound 8. We also obtained a more polar hydroxylation prod-
uct (7%). The structure of this product was determined by
comparison was performed without the CuÀO four-mem-
bered ring, but was constrained to conformations of the
Chem. Eur. J. 2004, 10, 6029 – 6042
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6033

B. Schçnecker et al.
FULL PAPER
The regio- and stereoselective functionalization of the 12-
position in steroid skeletons is not a trivial problem. Related
synthetic methods are very scarce, with the application of
[14]
Breslowꢁs remote oxidation method and the employment
of a manganese(iii) porphyrin attached through a spacer,
whereby a 3a-hydroxyandrostane could be hydroxylated
(
phenyliodosobenzene as oxidant) in the 12a-position, being
[15]
one of the few methods having been reported.
Hydroxylation of IMPY-camphor 12: After this successful
hydroxylation of nonactivated CH groups, we were interest-
2
ed in uncovering routes to hydroxylate a nonactivated CH3
group. According to our experience, an IMPY ligand pos-
sessing a methyl group in the g-position with respect to the
central nitrogen atom, and with the described six-membered
ring plane arrangement of the hydrogen atoms, should be
suitable for such a hydroxylation procedure. The camphor
molecule should fulfil all such conditions and was thus
chosen as a model compound in the form of (1R)-camphor
11 (Scheme 3).
Figure 5. X-ray crystal structure of the 13a-configured steroid 8.
1
13
detailed H and C NMR spectroscopic analysis to be the
epimeric 12a-hydroxy-17-ketone 10. This rather unexpected
result can be rationalized in terms of the two different C-
[
13a]
ring conformations
discussed above. Normally, such com-
2
pounds with an sp -hybridized C17 atom possess a C-ring
chair conformation (see Figure 4). A 12b-hydroxylation
seems to be possible in this conformation. Alternatively, a
conformation with a twist-boat C-ring should permit a way
for compound 6 to undergo a 12a-hydroxylation (Figure 6).
[16]
The IMPY derivative 12 is a known compound. In con-
trast to the 17-IMPY steroidal derivative, 12 is stable under
chromatographic conditions. Using initially method B, only
small amounts (3.7%) of a more polar compound could be
detected. In the high-resolution mass spectrum, the M+1
1
peak was consistent with a hydroxylated product. The H
NMR spectrum showed signals for only two methyl groups,
and an additional pair of doublets due to a CH group at
2
d = 3.62and 4.01 ppm, indicating that one methyl group
had been hydroxylated. Repeating the experiment according
to method A, this new compound could be obtained in a
yield of 31%. Further detailed NMR experiments confirmed
the expected structure 13, bearing a 10-hydroxy group
(
Scheme 3). Hydrolysis of the IMPY group of 13 gave the
Figure 6. Model for the copper–oxygen complex of the 13a-configured
IMPY steroid 6 adopting a C-ring twist-boat conformation and forming a
plane through the atoms N1, Cu1, O1, C13, C17.
1
known (1R)-10-hydroxy-camphor 14. The H NMR spec-
trum of 14 was identical to that of the racemic form.
Compound 14 is an interesting chiral source, obtained by
way of a three-step synthesis starting from (1R)-camphor, as
has recently been described.
We now possess four IMPY ligands that can be successful-
ly used in hydroxylations. Three of them can be effectively
hydroxylated using method A (3, 6, 12). Method B is better
only in the case of the 17-IMPY-3-methoxy-estra-1,3,5(10)-
triene 1 (see Scheme 1). We can only speculate about the
reasons for these differences. Possibly, two interdependent
oxidizing species, the concentrations of which are method-
dependent and, in addition, possess different arrangements
relative to the hydrogen atoms that must be abstracted, may
be responsible for these results.
[17]
[18]
[19]
The model structure in Figure 6 places the O1 oxygen at a
distance of 1.23 Š from the 12a-hydrogen. The 12a-H is
also displaced by 1.06 Š from the least-squares plane
through atoms N1 (0.09), Cu1 (0.12), O1 (0.10), C13 (0.09),
and C17 (0.02). Starting from the C-ring twist-boat confor-
mation (Figure 6), the torsion angle C12-C13-C17=N1 was
forced by a torsion constraint to adopt distinct values of
À208 to À608 in 108 increments. All the remaining internal
degrees of freedom in the structure were allowed to relax
with the exception of the N1-C-C-N2planarity. The calcula-
tions indicate that the 12a-hydrogen atom can be moved
reasonably well into the CuÀO complex plane (distance of
1
2aH from plane of about 0.2Š) with an associated energy
Hydroxylations with AMPY ligands: Aminomethylene com-
pounds (AMPY ligands) were chosen for additional experi-
ments because of their similarity to IMPY ligands. In con-
trast to the IMPY ligands from ring ketones (see Scheme 1),
the AMPY ligands obtained from ring amines with pyridine-
2-carboxaldehyde possess ring CÀN single bonds (see 16 and
À1
requirement of approximately 4 kcalmol .
If we assume a C-ring chair conformation for the active
À
species with the PF6 ion and an equilibrium of chair and
twist-boat conformations for the species with the triflate
anion, the obtained 12a-hydroxylation results can be under-
stood. The results from this last example clearly underline
the importance of the conformation in the hydroxylation
process.
21; Scheme 4). Recently, we were able to show through X-
ray analysis that such imines prefer a conformation with a
small Hgem-C-N=C torsional angle.
[20]
The stereochemical
6034
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 6029 – 6042

Intramolecular g-Hydroxylations in Copper Complexes
6029 – 6042
(
Scheme 4). The solid-state
structure of the corresponding
imine 16 exhibits the expected
small torsional angle for 17bH-
C17-17aN=C (9.88) and the E
configuration of the C=N
double bond was confirmed.
The results of systematically
searching the conformational
space of the AMPY structure in
steroid 16 by MMFF94 force-
field calculations are shown in
Figure 7.
The conformation found to
have the lowest energy is quite
close to the solid-state structure
determined
experimentally.
These two conformations are
superimposed on the right-
hand-side of Figure 7. Note that
both the crystal structure and
the calculated minimum-energy
structure have two features in
common: 1) the lone pairs of
the aminomethylenepyridine ni-
trogens N1 and N2are oriented
in opposite directions (angle 2
being calculated as 1808, and
measured as 1878 from the crys-
tal structure) and 2) the 17b-hy-
drogen is almost coplanar with
the 17a-AMPY group. A con-
Scheme 4. g-Hydroxylations with 17a- and 16a-AMPY ligands of the estra-1,3,5(10)-triene series. a) Pyridine- formational change from the
-carbaldehyde, MeOH, 608C; b) NaBH , CH OH/THF; c) 1. Cu(CH CN) PF , acetone, Ar; 2. O ; d) 1.
Cu(CF SO , acetone; 2. benzoin, N(C , Ar; 3. O ; e) 1. NaBH , CH OH; 2. NH OH, H O; 3. chromatog-
raphy on silica gel. f) 1. NH OH, H O; 2. chromatography on silica gel.
2
4
3
3
4
6
2
minimum-energy
structure
3
3
)
2
2
H
5
)
3
2
4
3
4
2
(
shown in Figure 7) to the ap-
4
2
propriate conformation for
copper complexation indicated
outcome of the cyclopropanation reaction of a,b-unsaturat-
ed imines also confirmed this conformation in solution.
in Figure 8 requires, according to the MMFF94 force field,
8.3 kcalmol for the AMPY steroid, without taking into ac-
[21]
À1
count the energy needed for copper complexation.
Hydroxylation of 17a-AMPY compound 16: We started our
investigations with the quasi-axial 17a-amine 15
In the conformation shown in Figure 8, abstraction of the
14a-H should be possible. The distance between 14a-H and
[22]
Figure 7. Conformational space of the model for AMPY steroid 16 (torsion angle 1: C13-C17-N=C; angle 2: N=C-CPy-NPy) with color-coded MMFF94
À1
energy in kcalmol (left) and superposition (right) of crystal structure (red structure related to red cross left) and calculated energy-minimum structure
(
blue structure corresponds to blue cross left).
Chem. Eur. J. 2004, 10, 6029 – 6042 www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6035

B. Schçnecker et al.
FULL PAPER
Following method A, 18 was isolated in almost 50% yield.
This result clearly confirmed our assumption that AMPY li-
gands can also be successfully used to hydroxylate nonacti-
vated CÀH bonds.
In a second experiment, the reaction mixture for the hy-
droxylation of 16 was hydrolyzed and separated. In this way,
the expected (and hitherto unknown) 1,3-amino alcohol 19
[
17a-amino-14a-hydroxy-3-methoxy-estra-1,3,5(10)-triene]
could be isolated in a yield of 46%. By using CH OH, ace-
3
tone, or dioxane as the solvent instead of CH Cl , we ob-
2
2
tained comparable yields. For convenience, in subsequent
experiments acetone was used as the solvent in both meth-
ods A and B.
Figure 8. Model for the copper–oxygen complex of the AMPY steroid 16
in a conformation forming a plane through the six atoms N1, Cu1, O1,
1
4a-H, C14, C17 (C13 out of this plane).
Hydroxylation of 16a-AMPY and 3a-AMPY steroids 21
and 25: To find further examples of hydroxylations of
AMPY ligands with a H-atom at a tertiary g-C-atom, we
the oxygen atom O1 is 1.16 Š. The least-squares plane
through the following six atoms has a root-mean-square de-
viation of 0.04 Š and the following individual displacements
[23]
started with the 16a-amine 20
(Scheme 4) and with 3a-
[22]
amino-5a-cholestane 24 (Scheme 5).
(
(
in Š) above/below the plane: N1 (0.05), Cu1 (0.01), O1
0.05), 14a-H (0.02), C14 (0.04), C17 (0.07). The carbon C13
The ligands 21 and 25 were obtained as pure crystalline
compounds. Assuming the more stable E configuration of
the C=N double bond and that the discussed imine confor-
mation is preferred, both ligands have a similar orientation
of the part needed for complexation with respect to the hy-
drogens at the tertiary g-C-atoms (14a-H for 21 and 5a-H
for 25), as in compound 16 (Figure 8). The steric relation-
ships and the six-membered ring planes are shown in
Figure 9.
is displaced by 0.86 Š from this plane. This model geometry
is in excellent agreement with the proposed stereochemical
requirement for a successful 14-H abstraction. For the
AMPY ligand (Figure 8), the b-C atom (C13) lies out of the
six-membered ring plane (for the IMPY ligands the g-C
atom lies out of this plane). For abstraction of the 12a-hy-
drogen (g-CH group), a conformational change with an as-
sociated energy increase of 10.2kcalmol is required; this
would move the O1 oxygen atom to a distance of 0.65 Š
from 12a-H (not shown).
2
À1
A common steric feature of all three ligands is a nearly
axial hydrogen at a tertiary g-C-atom in a 1,3- disposition
relative to the central nitrogen atom. Interestingly, in 16 and
Hydroxylation of the AMPY ligand 16 (Scheme 4) was in-
vestigated by means of method B. The reaction mixture was
directly reduced with NaBH in CH OH so that the stable
25 further axial hydrogen atoms (belonging to a CH group)
2
are in a 1,3-relationship with respect to the central nitrogen
(12a-H of 16 and 1a-H of 25). Using method A for the hy-
droxylation of 21 and 25 gave, after reduction with NaBH4,
the reduced ligands (22 and 26) and the expected hydroxyla-
tion products 23 (with a 14a-hydroxy group) and 27 (with a
5a-hydroxy group), in yields of 18 and 20%, respectively, as
determined by MS and detailed NMR spectroscopy. The
lower yields as compared to the hydroxylation of 16 may
4
3
2-pyridylmethylamino compounds could be isolated by chro-
matography after decomplexation. In addition to the re-
duced ligand 17 (main product), a more polar compound
could be isolated in 8% yield. This was identified by mass
spectrometry and detailed NMR analysis as the expected
14a-hydroxylated 17a-pyridylmethylamino compound 18.
Scheme 5. g-Hydroxylation of 3a-AMPY-5a-cholestane. a) Pyridine-2-carbaldehyde, MeOH, 608C; b) NaBH
Ar; 2. O ; d) 1. NaBH , CH OH; 2. NH OH, H O; 3. chromatography on silica gel.
4 3 3 4 6
, CH OH; c) 1. Cu(CH CN) PF , acetone,
2
4
3
4
2
6036
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 6029 – 6042

Intramolecular g-Hydroxylations in Copper Complexes
6029 – 6042
nese(iii) porphyrins linked to cyclodextrins through
[26]
spacers.
Conclusion
Using IMPY and AMPY compounds, we have developed a
protocol for the hydroxylation of nonactivated CH, CH2,
and CH groups in g-positions with respect to the central ni-
3
trogen. IMPY and AMPY groups can serve as auxiliaries for
the starting oxo and primary amino compounds. After the
hydroxylation procedure and hydrolysis, 3-hydroxy-1-oxo
and 3-hydroxy-1-primary amino compounds can be ob-
tained. Another possibility is simple reduction of the IMPY
and AMPY groups after the hydroxylation procedure, which
yields 3-hydroxy-1-(aminomethyl)-a-pyridines.
A clear advantage of this procedure is the simple intro-
duction of IMPY and AMPY groups into complex mole-
cules. The ensuing introduction of a hydroxy group at a non-
activated 3-position is also possible by way of a relatively
simple procedure using copper(i) salts and molecular
oxygen. Although the influence of the means of preparation
of the copper(i) complexes [starting with copper(i), meth-
od A; or copper(ii) and reduction, method B] needs to be
further investigated, conformational analyses based on
force-field calculations and X-ray crystal structure results
contribute to an understanding of the stereochemical re-
quirements of the oxidizing species in relation to the hydro-
gen that must be abstracted. On this basis, we suggest a
simple procedure to predict if a hydroxylation procedure
will be successful and we summarize the yields of our hy-
Figure 9. Steric relationships of AMPY groups and H atoms at g-C
atoms.
possibly be accounted for by small structural differences in
the active copper–oxygen complexes relating to the hydro-
gen atom that must be abstracted. Here, method A works
best, as demonstrated by the fact that an attempt to
hydroxyllate 25 according to method B led only to isolation
of the reduced ligand 26.
These results confirm that AMPY ligands are suitable for
copper-mediated hydroxylations of nonactivated CÀH bonds
at tertiary C-atoms. Prerequisites for a successful reaction
are a defined arrangement of the hydrogen atom with re-
spect to the active copper–oxygen species, as well as the car-
rying out of the reaction with a copper(i) salt (method A).
The question as to whether the
droxylation experiments for both methods A and
(Table 1).
B
hydroxylation of nonactivated
Table 1. Collected results of hydroxylations
CH groups is also possible with
2
Compound
Torsion
Torsion angle [8]
value [a]
Yields
[%]
these AMPY ligands cannot be
completely answered with these
model compounds. In these few
angle [a]
X-ray
(or force field)
examples, a hydroxylation of 17-oxo-3-methoxy-estra-1,3,5(10)-triene
O=C17-C13–12bH
N1=C17-C13-12bH
8.0
6.0 (12.3)
[
7]
the 12-CH group in 16 or the
1
3
5
17-IMPY
12bOH 17-one
A: 29
B: 50
A: 18
B: 11
2
1
-CH group in 25 could not be
2
17a-IMPY (d-homo)
N=C17-C13-12bH
9.3
4
achieved.
A few inter- and intramolecu-
O=C17-C13-12bH
N=C17a-C13-12bH
À14.4
lar methods for the hydroxyla- 6 17-IMPY (13a)
tion of nonactivated CÀH
(À18.0)
8
A: 34
B: 6
8
O=C17-C13-12bO
N=C2-C1-10H
0.8
9.6
n. d.
bonds at tertiary C atoms are
camphor oxime
known, and these have been re-
12 IMPY-camphor
13
18
A: 31
B: 4
A: 50
B: 8
viewed by Parish and co-work-
[
24]
ers. Most of them are not re- 16 17a-AMPY
N1-C17-C14-14aH
7.0 (6.2)
gioselective. External oxidants
[24]
[24]
19
23
27
A: 46
A: 18
A: 20
B: 0
are ozone, the Gif system,
2
2
1 16a-AMPY
5 3a-AMPY
n. d.
n. d.
[
24]
dioxiranes,
and
chromyl
[
24]
[14a]
esters.
Benzophenones,
III
[15,24]
Mn porphyrins,
boxylic acids
and car-
have also
[
10,25]
been employed as intramolecular groups for oxygen trans-
fer. Recently, Breslow and co-workers have described a cat-
alytic process for hydroxylations involving the use of manga-
The four atoms defining the torsional angle [a] are part of
the seven-membered transition state and should be nearly
coplanar for a successful hydroxylation (small [a] values).
Chem. Eur. J. 2004, 10, 6029 – 6042
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6037

B. Schçnecker et al.
FULL PAPER
The definition, beginning with the central nitrogen, is given
in Figure 10. The g-C atom for the IMPY and the b-C atom
for the AMPY compounds, which are not in the plane, are
omitted. At the end is the H atom that has to be abstracted.
Furthermore, the configuration of the imino bond and the
orientation of the lone pairs of the two nitrogen atoms for
binding the copper ions have to be taken into account.
roids with AMPY and IMPY groups in the 17-position. In grid searching,
a geometry optimization was performed for each grid point, whereby the
two selected torsion angles were systematically varied but then kept con-
strained in the optimization of the remaining internal coordinates.
AMPY and IMPY steroid models lacking the 3-methoxy function were
used. The starting conformations were built without using crystal struc-
ture information and were energy-minimized using the same force-field
set-up (maximum number of iterations = 10000; termination with an
energy gradient of 0.001). All energy values provided in this article are
based on strain energies taken from MMFF94 force-field calculations
and are quoted relative to the lowest-energy conformation. To display
the energy contour maps, the 900 conformations with the lowest energies
were selected from a total of 1369 calculated conformations. For least-
squares alignments of steroid structures, all steroid backbone atoms were
taken into account.
In the process of modeling the 13a-configured IMPY steroid, uncon-
strained in vacuo molecular dynamics (MD) computations of 100 ps were
employed instead of grid searches in order to better capture the confor-
mational space of the rings (temperature = 300 K; NTV ensemble; time
interval step = 1 fs; distance-dependent dielectric function; non-bonded
cut-off = 8 Š; nonbonded list update every 25 fs; no periodic boundary
conditions). As starting geometries for the two MD simulations, both the
C-ring chair and the C-ring twist-boat conformations were constructed
and minimized applying the MMFF94 force field. These two basic ring
Figure 10. Definition of the torsional angle [a].
[
33]
conformations have been found previously in the case of 13a steroids.
The angle [a] can be determined from molecular models
or from X-ray data for the IMPY or AMPY compounds.
However, the starting carbonyl or amino compounds or de-
rivatives can also be used (see Table 1). In this manner, the
likely products of hydroxylations of new compounds can be
predicted in a simple manner.
An average structure from the simulation for each basic C-ring confor-
mation as well as some representative dynamics snapshots were selected;
the conformation within the 17-side chain was then adopted so as to
allow H abstraction, and these structures were finally energy-minimized
once more. The conformations of five- and six-membered rings were
[
34]
judged by using asymmetry parameters DC
s
and DC
2
and phase angles
[
35]
of pseudorotation D.
To model the binuclear complex with the four-membered ring containing
copper and oxygen, the crystal structure of bis[aqua-(m -hydroxo)-(2,2’-bi-
pyrimidinyl-N,N’)-copper] dinitrate tetrahydrate (CSD refcode:
PEMPEC) was selected. This structure provides a Cu–O distance of
.94 Š.
2
[
36]
Experimental Section
[37]
1
General methods: Melting points were measured on a Botius micro
melting point apparatus and are corrected values. Mass spectra were de-
termined on an AMD 402Intectra instrument with either direct electron
impact (EI) or electrospray ionization (ESI) at 70 eV. Optical rotations
were measured at room temperature in the solvents given in the individu-
al procedures with a Polamat A (Carl Zeiss Jena) polarimeter and are
All molecular modeling calculations were performed on an SGI Octane
R14000 computer (500 MHz, main memory 1536 Mbytes) employing the
SYBYL molecular modeling environment in software version 6.9.
ꢂ
[38]
Synthesis of the IMPY ligands
1
7a-(N-2-Pyridylmethyl)imino-d-homo-3-methoxy-estra-1,3,5(10)-triene
[
12c]
À1
À1
(
3): A mixture of 3-methoxy-d-homo-estra-1,3,5(10)-triene-17a-one 2
given in units of g100 mL . Elemental analyses were performed with a
1
13
(
2.0 g, 6.9 mmol), 2-(aminomethyl)pyridine (3.5 mL, 34.7 mmol), and a
CHNS-932(LECO) instrument. H and C NMR spectra were recorded
on either a Bruker AC 250 or a DRX-400 spectrometer, in CDCl or in
( H NMR 250 MHz, 400 MHz; C NMR 62.5 MHz, 100 MHz).
catalytic amount of p-toluenesulfonic acid (30 mg) was dissolved in tolu-
ene (30 mL) and refluxed for 9 h in a Dean–Stark apparatus. The reac-
tion mixture was then cooled to room temperature and diluted with ethyl
acetate. The organic layer was washed twice with saturated aqueous
NaHCO solution and water, and dried over Na SO . The solvent was
3 2 4
evaporated and the yellow oily crude product was purified by crystalliza-
3
1
13
2 2
CD Cl
Signals were assigned with the aid of DEPT, COSY-DQF, TOCSY,
NOESY, HMQC, HMBC, and HSQC-TOSCY experiments. All reactions
were carried out under an inert atmosphere. The reactions were moni-
tored by TLC on aluminum sheets coated with silica gel 60 F254 (Merck),
thickness 0.2mm, detection under UV light ( 25 4 nm) or by spraying with
tion from ethyl acetate to give 17-imine 3 as light-yellow crystals (2.28 g,
2
D
4
a solution of P
2
O
5
·24MoO
3
·H
2
O (2.5 g/50 mL; 42% H
3
PO
4
) and heating
87%). M.p. 95–988C (ethyl acetate); [a]
= 21.9 (c = 0.4 in MeOH);
): d = 1.10 (s, 3H; 18-H ), 2.84 (m, 2H; 6-
O), 4.63 (m, 2H; CH Py), 6.61 (d, J = 2.7 Hz, 1H;
1
at 1708C. MPLC was performed on Lichroprep Si 60, 15–25 mm (Merck).
Solvents were purified, dried, and distilled according to conventional
methods.
H NMR (250 MHz, CD
), 3.75 (s, 3H; CH
2
Cl
2
3
3
H
2
3
2
3
3
3
4-H), 6.68 (dd, J = 2.7 Hz, J = 8.6 Hz, 1H; 2-H), 7.23 (d, J = 8.6 Hz,
H; 1-H), 7.19, 7.56, 7.68, 8.50 ppm (4m, 4”1H; 4”HPy); MS (EI): m/z
%): 388 (100) [M ]; HRMS: calcd. for C26
1
(
Crystal structure analysis: Intensity data for compounds 3, 16, and 8 were
collected on a Nonius KappaCCD diffractometer using graphite-mono-
chromated MoKa radiation. Data were corrected for Lorentz and polari-
+
H
32
N
2
O: 388.2611; found:
3
88.2615.
[
27,28]
[31]
À1
zation effects, but not for absorption effects.
The structures were
Crystal data for 3:
C
26
3
H
32
N
2
O, M
r
= 388.54 gmol , colorless prism,
[
29]
solved by direct methods (SHELXS ) and refined by full-matrix least-
size 0.03”0.03”0.02mm , monoclinic, space group P2
b = 23.1923(9), c = 7.1135(3) Š, b = 95.585(2)8, V = 1082.15(7) Š ,
1
, a = 6.5906(2),
o
[30]
3
squares techniques against F2 (SHELXL-97 ). For compound 8, the hy-
drogen atom of the hydroxy group was located by difference Fourier syn-
thesis and refined isotropically. The other hydrogen atoms were included
at calculated positions with fixed thermal parameters. All non-hydrogen
atoms were refined anisotropically. XP (Siemens Analytical X-ray In-
struments, Inc.) was used for structure representations.
À3
À1
T = À908C, Z = 2, 1calcd = 1.192gcm , m(MoKa) = 0.72cm , F(000) =
420, 4343 reflections in h(À8/8), k(À29/27), l(À9/9), measured in the
range 2.888 ꢀVꢀ27.498, completeness Vmax = 99.6%, 4343 independent
[30]
o o
reflections, 3164 reflections with F > 4s(F ), 262 parameters, 1 restraint,
[
31]
2
2
R1obs = 0.051, wR obs = 0.111, R1all = 0.082, wR all = 0.126, GOOF =
[
32]
1.016, Flack parameter 1.7(18), largest difference peak and hole: 0.151/
Modeling and conformational analysis: The MMFF94 force field with
MMFF94 atomic charges and the grid conformational search option for
two torsion angles ranging from 08 to 3608 in angular increments of 108
was employed for the conformational analysis of the 13b-configured ste-
À3
À0.152eŠ
.
17-(N-2-Pyridylmethyl)imino-3-methoxy-13a-estra-1,3,5(10)-triene (6): 2 -
(Aminomethyl)pyridine (3.6 mL, 35 mmol) and 3-methoxy-13a-estra-
6038
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 6029 – 6042

Intramolecular g-Hydroxylations in Copper Complexes
6029 – 6042
[
13a]
1
(
,3,5(10)-triene-17-one (5;
30 mL) for 20 h as described for the synthesis of 3. The sticky brown
crude product was crystallized from ethyl acetate to give pure 17-imine 6
2.0 g, 7 mmol) were reacted in toluene
(0.1 mL, 1.5 mmol) were reacted in absolute methanol (20 mL) as descri-
bed for the synthesis of 16. The 16a-AMPY compound 21 was obtained
as white crystals (255 mg, 68%) after recrystallization from methanol.
2
4
1
(
2.35 g, 89%) as a light-yellow amorphous solid. M.p. 115–1188C (ethyl
D
3
M.p. 94–978C (methanol); [a] = +112.5 (c = 0.8 in CHCl ); H NMR
2
D
4
1
acetate); [a]
CD
=
À48.0 (c
=
1.5 in MeOH); H NMR (250 MHz,
), 2.80 (m, 2H; 6-H ), 3.74 (s, 3H;
Py), 6.58 (d, J = 2.7 Hz, 1H; 4-H), 6.68 (dd,
3 3 2
(250 MHz, CDCl ): d = 0.87 (s, 3H; 18-H ), 2.83 (m, 2H; 6-H ), 3.76 (s,
3
2
Cl
2
): d = 1.09 (s, 3H; 18-H
3
2
3
3H; CH O), 4.10 (m, 1H; 16b-H), 6.64 (d, J = 2.7 Hz, 1H; 4-H), 6.71
3
3
3
3
CH
3
O), 4.57 (m, 2H; CH
2
(dd, J = 2.7 Hz, J = 8.6 Hz, 1H; 2-H), 7.21 (d, J = 8.6 Hz, 1H; 1-H),
3
3
3
J = 2.7 Hz, J = 8.6 Hz, 1H; 2-H), 7.20 (d, J = 8.6 Hz, 1H; 1-H), 7.09,
.45, 7.60, 8.46 ppm (4m, 4”1H; 4”HPy); MS (EI): m/z (%): 374 (100)
M ]; elemental analysis calcd (%) for C25
.07, N 7.48; found: C 79.72, H 8.09, N 7.85.
1R)-2-(N-2-Pyridylmethyl)iminobornane (12):
3.0 g, 19.7 mmol) and 2-(aminomethyl)pyridine (4.0 mL, 39.4 mmol)
7.28, 7.71, 7.98, 8.62 (4m, 4”1H; 4”H ), 8.26 ppm (s, 1H, N=CH); ele-
Py
7
[
8
mental analysis calcd (%) for C H N O (374.5): C 80.17, H 8.07, N 7.48;
2
5
30
2
+
H
30
N
2
O (374.5): C 80.17, H
found: C 79.72, H 8.07, N 7.07.
1
6a-(N-2-Pyridylmethyl)amino-3-methoxy-estra-1,3,5(10)-triene
(22):
[
16]
(
(
(1R)-Camphor 11
Compound 21 (375 mg, 1.0 mmol) and NaBH
4
(190 mg, 5.0 mmol) were
allowed to react in absolute MeOH and THF as described for the reduc-
were dissolved in xylene (100 mL), and a catalytic amount of p-toluene-
sulfonic acid (40 mg) was added. The reaction mixture was refluxed for
tion of 16. Crystallization of the product from n-heptane gave 22 as a
24
white solid (347 mg, 92%). M.p. 87–91 8C (n-heptane); [a] = +63.1 (c
D
3
6 h in a Dean–Stark apparatus. After the mixture was cooled to room
temperature, it was diluted with ethyl acetate, washed twice with saturat-
ed aqueous NaHCO solution and water, dried, and concentrated. The
oily residue was chromatographed on silica gel eluting with CH Cl
CH OH (85:15) to afford the (1R)-camphor imine 12 as a yellow oil
1
=
0.7 in CHCl
.81 (m, 2H; 6-H
H; CH Py), 6.60 (d, J = 2.7 Hz, 1H; 4-H), 6.68 (dd, J = 2.7 Hz, J =
.6 Hz, 1H; 2-H), 7.11–7.28 (m, 3H; 2”HPy and 1-H), 7.61 and 8.54 ppm
3
); H NMR (250 MHz, CDCl
3
): d = 0.76 (s, 3H; 18-H
3
),
2
2
8
2
), 3.36 (m, 1H; 16b-H), 3.75 (s, 3H; CH
3
O), 3.85 (m,
3
3
3
3
2
2
2
/
+
3
(
2m, 2”1H; 2”H Py); MS (ESI): m/z (%): 377 (100) [M +H]; HRMS
+
2
4
1
(
3.4 g, 72%). [a] = À7.3 (c = 0.8 in MeOH); H NMR (250 MHz,
D
25 33 2
(ESI): calcd for C H N O [M +H]: 377.2913; found: 377.2607.
3 3 3 3
CDCl ): d = 0.75 (s, 3H; CH ), 0.92(s, 3H; CH ), 1.02(s, 3H; CH ),
1
3
3a-(N-2-Pyridylmethylene)amino-5a-cholestane (25): 3a-Amino-5a-cho-
4
.55 (m, 2H; CH
2
Py), 7.09, 7.43, 7.62, 8.48 ppm (4m, 4”1H; 4”HPy);
): d = 11.4 (CH ), 19.0 (CH ), 19.6 (CH ), 27.4
), 36.1 (CH ), 43.9 (CH), 47.4 (C ), 54.2(C ), 57.4
Py), 121.6, 121.7, 136.6, 148.9, 160.4 (5”CPy), 185.3 ppm (N=C );
C
[22]
lestane (24;
1.94 g, 5.0 mmol) and pyridine-2-carbaldehyde (0.5 mL,
NMR (62.5 MHz, CDCl
3
3
3
3
7
.5 mmol) were reacted in absolute methanol (100 mL) as described for
(
CH
2
), 32.2 (CH
2
2
q
q
the synthesis of 16. The solvent was then evaporated to leave a yellow
oil. The 3a-AMPY compound 25 was obtained as white crystals (2g,
(
NCH
2
q
+
HRMS (ESI): calcd for C16
Synthesis of the AMPY ligands
7a-(N-2-Pyridylmethylene)amino-3-methoxy-estra-1,3,5(10)-triene (16):
23 2
H N [M +H]: 243.1861; found: 243.1862.
8
5%) after crystallization from methanol. M.p. 40–438C (methanol);
24
1
[
a]D
=
+20.1 (c = 1.2in CHCl
.65 (s, 3H; 18-H ), 0.85–0.97 (m, 12H; 4”CH
), 3.60 (m, 1H; 3b-H), 7.26, 7.69, 8.07, 8.60 (4m, 4”1H; 4”HPy),
3
); H NMR (250 MHz, CDCl
3
): d =
1
0
H
8
3
3
, 19-H , 21-H , 26-H
3
3
3
, 2 7-
[22]
A solution of the 17a-amine 15 (570 mg, 2.0 mmol) in absolute metha-
nol (30 mL) containing pyridine-2-carbaldehyde (0.14 mL, 2.9 mmol) was
stirred at 608C under an argon atmosphere for 2h. The solution was then
concentrated to half of its original volume and allowed to cool to room
temperature. The crystallized product was collected by filtration, washed
with cold methanol, dried in vacuo, and recrystallized from methanol to
give the 17a-AMPY compound 16 (602mg, 80%) as colorless crystals.
3
+
.37 ppm (s, 1H, N=CH); MS (EI): m/z (%): 476 (100) [M ]; elemental
52 2
analysis calcd (%) for C33H N (476.4): C 83.12, H 10.99, N 5.88; found:
C 83.03, H 10.82, N 5.86.
3
1
CH
a-(N-2-Pyridylmethyl)amino-5a-cholestane (26): Imine 25 (476 mg,
mmol) and NaBH (190 mg, 5 mmol) were allowed to react in absolute
OH as described for the synthesis of 17. 26 was obtained as white
4
2
D
4
1
3
M.p. 118–1218C (methanol); [a] = À82.9 (c = 0.8 in CHCl
3
); H NMR
), 3.42(m,
crystals after recrystallization from CH
778C (MeOH); H NMR (250 MHz, CDCl
3
OH (430 mg, 90%). M.p. 75–
): d = 0.62(s, 3H; CH ), 0.77
), 0.85 (m, 3H; CH ), 2.87 (m, 1H;
Py), 7.11, 7.30, 7.60, 8.52ppm (4m, 4”1H; 4”
Py); C NMR (62.5 MHz, CDCl ): d = 11.5 (CH ), 12.0 (CH ), 18.6
(
250 MHz, CDCl
3
): d = 0.85 (s, 3H; 18-H
3
), 2.86 (m, 2H; 6-H
2
1
3
3
3
1
(
7
(
3
H; 17b-H), 3.76 (s, 3H; CH O), 6.62(d, J = 2.7 Hz, 1H; 4-H), 6.67
dd, J = 2.7 Hz, J = 8.6 Hz, 1H; 2-H), 7.17 (d, J = 8.6 Hz, 1H; 1-H),
.28, 7.70, 8.03, 8.61 (4m, 4”1H; 4”HPy), 8.26 ppm (s, 1H, N=CH); MS
ESI): m/z (%): 397 (100) [M +Na]; elemental analysis calcd (%) for
O (374.5): C 80.17, H 8.07, N 7.48; found: C 80.39, H 7.83, N
3
3
3
(m, 9H; 3”CH
3
), 0.83 (m, 3H; CH
3
3
3
H
b-H), 3.87 (m, 2H; CH
2
1
3
+
3
3
3
(
(
(
(
(
CH
CH
CH
3
2
2
), 20.7 (CH
), 28.0 (CH
), 35.5 (CH), 35.8 (CH), 36.2(CH
), 42.6 (C
2
), 22.5 (CH
), 28.2 (CH
3
), 22.7 (CH
), 28.8 (CH
3
), 23.8 (CH
), 32.0 (CH
), 36.2(C
), 52.4 (CH), 53.1 (CH
CH), 56.6 (CH), 121.7 (CHPy), 121.3 (CHPy), 136.3 (CHPy), 149.1 (CHPy),
2
), 24.1 (CH
), 32.7 (CH
2
), 26.1
), 33.4
25 30 2
C H N
7
2
2
2
2
2
.37.
2
q
), 39.5 (CH
2
), 39.6
[
31]
À1
Crystal data for 16:
C
25
3
H
30
N
2
O, M
r
= 374.51 gmol , colorless prism,
CH), 40.1 (CH
2
q
2
), 54.3 (CH), 56.3
size 0.05”0.04”0.03 mm , orthorhombic, space group P2
.0529(2), b = 13.7690(3), c = 16.6758(4) Š, V = 2078.63(8) Š , T =
À908C, Z = 4, 1calcd = 1.197 gcm , m(MoKa) = 0.73 cm , F(000) =
08, 4739 reflections in h(À11/11), k(À17/17), l(À21/21), measured in the
range 1.928 ꢀ V ꢀ 27.498, completeness Vmax = 99.8%, 4739 independ-
ent reflections, 3936 reflections with F > 4s(F ), 253 parameters, 0 re-
1
2
1
2
1
,
a
=
3
9
+
1
60.4 ppm (CPy); MS (ESI): m/z (%): 479 (100) [M +H]; HRMS: calcd
+
À3
À1
for C33
55 2
H N [M +H]: 479.4365; found: 479.4374; elemental analysis
8
54 2
calcd (%) for C33H N (478.4): C 82.85, H 11.30, N 5.86; found: C 82.63,
H 10.99, N 5.94.
o
o
2
2
Hydroxylation procedures with IMPY and AMPY ligands
Method A: Tetrakis(acetonitrile)copper(i) hexafluorophosphate
(1.2equiv) was added to a solution of 1 equivalent of the IMPY ( 3, 6, 12)
or AMPY ligand (16, 21, 25) in absolute acetone that had been degassed
with argon. The resulting brown solutions were stirred at room tempera-
straints, R1obs = 0.044, wR obs = 0.098, R1all = 0.060, wR all = 0.106,
GOOF = 1.023, Flack parameter À1.7(15), largest difference peak and
À3
hole: 0.147/À0.175 eŠ
1
NaBH
(
.
7a-(N-2-Pyridylmethyl)amino-3-methoxy-estra-1,3,5(10)-triene
(17):
4
(190 mg, 5 mmol) was added to a stirred solution of 17a-imine 16
ture. After 1 h, the argon atmosphere was replaced by an O
Pure O was then bubbled through the reaction mixtures for approxi-
mately 10 min. The solutions were then stirred for about 24 h under O
2
atmosphere.
375 mg, 1.0 mmol) in absolute MeOH (15 mL) and THF (5 mL) at room
temperature. After 90 min, the reaction mixture was poured into an ice/
water mixture and extracted with CH Cl . The organic phase was washed
2
2
.
2
2
with water, dried, and concentrated. The oily residue was crystallized
from n-heptane to give 17 as white crystals (300 mg, 80%). M.p. 79–818C
During this time, they turned dark green. The solvent was then distilled
off and the oily dark residues were worked-up as described below in the
respective syntheses.
2
D
4
1
(
n-heptane); [a]
=
+9.1 (c = 0.8 in CHCl
): d = 0.74 (s, 3H; 18-H ), 2.72 (m, 1H; 17b-H), 2.84 (m, 2H; 6-
), 3.75 (s, 3H; CH O), 3.86 (m, 2H; CH
3
); H NMR (250 MHz,
CDCl
H
4
H
3
3
Method B: Anhydrous copper(ii) triflate (1.2equiv) was added to a so-
lution of the IMPY or AMPY ligand (3, 6, 12 or 16, 21, 25; 1 equiv.) in
absolute acetone. The dark green solutions were stirred at room tempera-
ture for about 1 h. Under an argon atmosphere and with constant stirring,
benzoin (2equiv) and triethylamine (2equiv) were added. After 4 h,
3
2
3
2
Py), 6.63 (d, J = 2.7 Hz, 1H;
-H), 6.68 (dd, J = 2.7 Hz, J = 8.6 Hz, 1H; 2-H), 7.10–7.29 (m, 3H; 2”
Py and 1-H), 7.59 and 8.59 ppm (2m, 2”1H; 2”H Py); elemental analysis
3
3
calcd (%) for C25
H 8.88, N 7.19.
32 2
H N O (376.5): C 79.75, H 8.56, N 7.44; found: C 79.41,
pure O
solutions were stirred for a further 24 h under O
became dark green once more. After removing the solvent, dark, oily
2
was bubbled through the mixtures for 10 min. The yellow-brown
1
1
6a-(N-2-Pyridylmethylene)amino-3-methoxy-estra-1,3,5(10)-triene (21):
2
, during which they
[
23]
6a-Amine 20
(285 mg, 1.0 mmol) and pyridine-2-carbaldehyde
Chem. Eur. J. 2004, 10, 6029 – 6042
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6039

B. Schçnecker et al.
FULL PAPER
crude products were obtained, which were worked-up as described in
detail below.
synthesis of 4. Separation of the oily crude product by MPLC eluting
with n-hexane/ethyl acetate (75:25) gave 5 (68 mg, 24%), 8 (57 mg,
1
9%), and 12a-hydroxy-13a-estrone-3-methyl ether 10 (21 mg, 7%) as a
1
2b-Hydroxy-d-homo-3-methoxy-estra-1,3,5(10)-triene-17a-one (4): Fol-
colorless oil.
lowing method A, compound 3 (388 mg, 1 mmol) was reacted with
I
24
1
Cu (CH
product was first dissolved in ethyl acetate and then extracted three
times with NH OH (25%); the brown organic layer was washed with
brine, dried over Na SO , and concentrated. The residual dark brown oil
was then redissolved in methanol (20 mL) and treated with glacial acetic
acid (20 mL) at 908C for 6 h. The methanol was then removed, and the
mixture was poured into water and extracted with ethyl acetate. The
3
CN)
4
PF
6
(450 mg, 1.2mmol) in acetone ( 20 mL). The crude
10: [a]D = À3.5 (c = 1.4 in CHCl
3
); H NMR (400 MHz, CDCl
3
): d =
1.16 (s, 3H; 18-H
3
), 2.83 (m, 2H; 6-H
2
), 3.74 (s, 3H; CH O), 4.20 (m,
3
1H; 12b-H), 6.60 (d, 1H, J = 2.7 Hz; 4-H), 6.68 (dd, 1H, J = 2.7 Hz, J
4
1
3
= 8.6 Hz; 2-H), 7.15 ppm (d, 1H, J = 8.6 Hz; 1-H); C NMR (100 MHz,
CDCl ): d = 20.7 (C-18), 21.0 (CH ), 28.2 (CH ), 30.2(CH ), 33.7 (CH ),
34.0 (CH), 35.9 (CH ), 41.8 (CH), 46.6 (CH), 53.7 (C-13), 55.2(H CO),
69.3 (C-12), 111.7 (C-2), 113.6 (C-4), 126.7 (C-1), 131.9 (C-10), 138.1 (C-
5), 157.5 (C-3), 220.6 ppm (C-17); MS (ESI): m/z (%): 323 (100) [M
2
4
3
2
2
2
2
2
3
+
combined organic phases were washed with brine and dried (Na
Evaporation of the volatiles left a dark oil, which was purified and sepa-
2
SO
4
).
+
+Na]; HRMS (ESI): calcd for C19
H
24
O
3
Na [M +Na]: 323.1623; found:
rated by MPLC using Lichroprep Si 60, 15–20 mm, eluting with n-hexane/
ethyl acetate, 80:20 (column 200”35 mm, rate 25 mLmin ) to yield the
d-homo-17a-ketone (116 mg, 39%) and the 12b-hydroxy compound
323.1625.
À1
(
1S)-2-(N-2-Pyridylmethyl)imino-10-hydroxybornane (13): According to
method A, (1R)-IMPY-camphor 12 (1.00 g, 4.1 mmol) was allowed to
(
57 mg, 18%).
I
react with Cu (CH
crude product was dissolved in CHCl
tracted with 25% NH OH (3”40 mL). The yellow organic layer was
washed with brine, dried (Na SO ), and concentrated. The residue was
chromatographed on silica gel eluting with methyl tert-butyl ether
(MTBE) and MTBE/CHCl (1:1) to afford starting ligand 12 (530 mg,
3
CN)
4
PF
6
(1.83 g, 4.92mmol) in acetone (30 mL). The
Method B: Compound 3 (388 mg, 1 mmol) was allowed to react with
3
and the resulting solution was ex-
II
Cu (CF
3
SO
3
)
2
(440 mg, 1.2mmol), benzoin (4 25 mg, 2mmol), and tri-
4
ethylamine (0.3 mL, 2mmol) in acetone ( 20 mL). The work-up procedure
was performed in the same manner as described above. After MPLC, the
2
4
1
2b-hydroxy compound 4 (35 mg, 11%) was obtained as a white solid in
3
addition to the d-homo-17a-ketone 2 (161 mg, 54%).
53%) and 13 (330 mg, 31%) as a light-yellow oil.
2
D
4
4
: M.p. 156–1598C (n-hexane/ethyl acetate); [a] = À26.4 (c = 1.7 in
According to method B, compound 12 (560 mg, 2.3 mmol) was reacted
1
II
CHCl
H; 6-H
H), 6.61 (d, J = 2.7 Hz, 1H; 4-H), 6.70 (dd, J = 2.7 Hz, J = 8.6 Hz,
3
); H NMR (400 MHz, CDCl
3
): d = 1.16 (s, 3H; 18-H
3
), 2.85 (m,
with Cu (CF
3
SO
3
)
2
(1.0 g, 2.76 mmol), benzoin (980 mg, 4.6 mmol), and
2
2
), 3.67 (s, 1H; 12b-OH), 3.76 (s, 3H; CH
3
O), 4.10 (m, 1H; 12a-
triethylamine (0.7 mL, 4.6 mmol) in acetone (50 mL). The work-up pro-
cedure was carried out as described above and yielded an oil. Purification
by column chromatography yielded starting ligand 12 (317 mg, 57%) and
13 (22 mg, 4%).
3
3
3
3
13
1
H; 2-H), 7.19 ppm (d, J = 8.6 Hz, 1H; 1-H); C NMR (100 MHz,
CDCl ): d = 11.4 (C-18), 22.3 (CH ), 25.6 (CH ), 26.6 (CH ), 29.8 (CH ),
2.6 (CH ), 37.4 (CH ), 38.0 (CH), 40.8 (CH), 48.7 (CH), 53.5 (C-13),
5.2(H CO), 72.5 (C-12), 111.6 (C-2), 113.6 (C-4), 126.1 (C-1), 131.5 (C-
0), 137.4 (C-5), 157.7 (C-3), 219.2 ppm (C-17a); MS (ESI): m/z (%): 337
3
2
2
2
2
2
D
4
1
3
5
1
2
2
13: [a] = À13.0 (c = 2.0 in MeOH); H NMR (250 MHz, CDCl ): d =
3
3
3 3 2
0.89 (s, 3H; CH ), 0.99 (s, 3H; CH ), 3.82(m, 2H ; CH OH), 4.52(m,
2H; CH Py), 7.13, 7.39, 7.64, 8.48 ppm (4m, 4”1H; 4”H ); C NMR
1
3
2
Py
+
+
(
100) [M +Na]; HRMS (ESI): calcd. for
C
26
H
32
N
2
ONa [M +Na]:
3 3 3 2 2
(62.5 MHz, CDCl ): d = 18.9 (CH ), 20.5 (CH ), 27.0 (CH ), 28.7 (CH ),
3
37.1975; found: 337.1780.
2 q 2
36.0 (CH ), 44.9 (CH), 47.1 (C ), 57.2(C q), 57.5 (NCH Py), 62.8
1
2b-Hydroxy-3-methoxy-13a-estra-1,3,5(10)-triene-17-one (8): According
(CH
2
OH), 121.6, 121.8, 136.7, 148.9, 159.8 (5”CPy), 186.1 ppm (N=C );
q
+
to method A, the IMPY ligand 6 (374 mg, 1 mmol) was allowed to react
with Cu (CH
bed for the synthesis of 4. Separation of the oily crude product by
column chromatography eluting with n-hexane/ethyl acetate (75:25) gave
5
MS (ESI): m/z (%): 259 (100) [M +H]; HRMS (ESI): calcd for
C H N O [M +H]: 259.1810; found: 259.1808.
16 23 2
I
+
3
CN)
4
PF
6
(450 mg, 1.2mmol) in acetone ( 20 mL) as descri-
[
19]
(1R)-10-Hydroxy-camphor (14): Acetic acid (20 mL) was added to a
solution of compound 13 (260 mg, 1.0 mmol) in methanol (20 mL) and
the mixture was heated at 908C for about 6 h. The solution was then con-
centrated to dryness and the resulting crude product was purified by
column chromatography on silica gel eluting with methyl tert-butyl ether/
n-heptane (3:7) to give 14 (131 mg, 78%) as white crystals.
[
13a]
(74 mg, 26%) and 12b-hydroxy-13a-estrone-3-methyl ether
8
6
(
(
102mg, 34%) as white crystals. According to method B, compound
374 mg, 1 mmol) was reacted with Cu (CF SO ) (440 mg, 1.2mmol),
3 3 2
II
benzoin (4 25 mg, 2mmol), and triethylamine (0.3 mL, 2mmol) in ace-
tone (20 mL). The work-up procedure was performed as described for
24
1
1
4: M.p. 186–1908C (MeOH); [a]D
=
+25.9 (c = 1.7 in CHCl
3
); H
the synthesis of 4. After MPLC, 5 (122 mg, 43%) and 8 (19 mg, 6%)
NMR (250 MHz, CDCl ): d = 0.96 (s, 3H; CH
3.73 ppm (m, 2H; CH OH); C NMR (62.5 MHz, CDCl ): d = 19.3
3
3
), 0.98 (s, 3H; CH ),
3
2
4
were obtained. 8: M.p. 162–1658C (MeOH); [a] = +10.0 (c = 0.7 in
13
D
2
3
1
CHCl
3
); H NMR (400 MHz, CDCl
3
): d = 1.37 (s, 3H; 18-H
O), 4.27 (d, 1H, J =
0.8 Hz; 12b-OH), 6.60 (d, 1H, J = 2.7 Hz; 4-H), 6.70 (dd, 1H, J =
3
), 2.82 (m,
(
CH
2 q
), 60.6 (CH OH), 61.6 (C ), 221.0 ppm (C=O); MS (ESI): m/z (%):
+ +
3
), 20.8 (CH
3
), 26.0 (CH
2
), 26.7 (CH
2
), 43.5 (CH
2
), 44.0 (CH), 46.8
2
1
2
2 3
H; 6-H ), 3.69 (m, 1H; 12a-H), 3.75 (s, 3H; CH
(
C
q
1
1
91 (100) [M +Na]; HRMS (ESI): calcd for C10
91.1048; found: 191.4200.
4a-Hydroxy-17a-(N-2-pyridylmethyl)amino-3-methoxy-estra-1,3,5(10)-
16 2
H O Na [M +Na]:
1
3
.7 Hz, J = 8.6 Hz; 2-H), 7.19 ppm (d, 1H, J = 8.6 Hz; 1-H); C NMR
): d = 21.0 (C-18), 21.3 (CH ), 27.9 (CH ), 30.1 (CH ),
), 37.9 (CH ), 39.7 (CH), 41.4 (CH), 50.2(CH), 53.2(C-13),
CO), 76.2 (C-12), 111.8 (C-2), 113.7 (C-4), 126.6 (C-1), 131.0 (C-
0), 137.8 (C-5), 157.7 (C-3), 225.4 ppm (C-17); MS (ESI): m/z (%): 323
(
100 MHz, CDCl
3
2
2
2
1
3
5
1
4.5 (CH
2
2
triene (18): Following method A, 17a-AMPY ligand 16 (105 mg,
5.2(H
3
I
0
0
.28 mmol) was allowed to react with Cu (CH
.34 mmol) in acetone (30 mL). The crude product was dissolved in
(43 mg, 1.12mmol) was slowly added.
The reaction mixture was stirred at room temperature. After 1 h, H
0.5 mL) was added. The dark oily residue that remained after removal
3
of the solvent was redissolved in CHCl and the resulting solution was ex-
3
CN)
4
PF
6
(125 mg,
+
+
(
19 24 3
100) [M +Na]; HRMS (ESI): calcd for C H O Na [M +Na]:
MeOH (15 mL) and then NaBH
4
3
23.1623; found: 323.1624.
2
O
[
31]
À1
Crystal data for 8:
0
C
19
H
24
O
3
, M
r
= 300.38 gmol , colorless prism, size
, a = 7.0319(1),
(
3
.03”0.03”0.02mm , orthorhombic, space group P2
1
3
2
1
2
1
b = 9.3898(2), c = 23.4019(4) Š, V = 1545.18(5) Š , T = À908C, Z =
, 1calcd = 1.291 gcm , m(MoKa) = 0.86 cm , F(000) = 648, 3506 reflec-
tions in h(À9/9), k(À12/12), l(À30/30), measured in the range 3.028 ꢀ V
27.478, completeness Vmax = 99.6%, 3506 independent reflections,
023 reflections with F
.045, wR obs = 0.109, R1all = 0.057, wR all = 0.116, GOOF = 1.066,
tracted with 25% NH
washed with brine, dried over Na
4
OH (4”15 mL). The brown organic layer was
SO , and concentrated. The resulting
À3
À1
4
2
4
oily product was purified by preparative TLC with methanol as eluent to
yield 18 (55 mg, 50%) as a light-yellow oil in addition to the reduced
ligand 17 (11 mg, 10%). According to method B, compound 16 (191 mg,
.51 mmol) was allowed to react with Cu (CF
benzoin (217 mg, 1.02 mmol), and triethylamine (0.15 mL, 1.02 mmol) in
acetone (20 mL). The crude product was dissolved in MeOH (15 mL)
ꢀ
3
0
o
> 4s(F
o
), 203 parameters, 0 restraints, R1obs
=
2
2
II
0
3
SO
3
)
2
(222 mg, 0.61 mmol),
Flack parameter 1.2(12), largest difference peak and hole: 0.293/
À3
À0.363 eŠ
.
1
2a-Hydroxy-3-methoxy-13a-estra-1,3,5(10)-triene-17-one (10): Following
and reduced with NaBH
4
(116 mg, 3.06 mmol) as described above. After
method A, the IMPY ligand 6 (374 mg, 1 mmol) was reacted with
column chromatography on silica gel (CHCl3; CHCl /CH OH, 5:1;
3
3
I
[
Cu (CF
3
SO
3
)(CH
3
C
6
H
5
)] (620 mg, 1.2 mmol) in acetone (20 mL). The re-
CHCl
3 3
/CH OH, 4:1) 15 mg (8%) of 18 and 107 mg (56%) of the reduced
action mixture was worked-up in a similar manner as described for the
ligand 17 were obtained.
6040
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 6029 – 6042

Intramolecular g-Hydroxylations in Copper Complexes
6029 – 6042
2
D
4
1
+
1
0
3
(
7
8: [a] = +37.4 (c = 1.0 in MeOH); H NMR (250 MHz, CDCl
3
): d =
158.6 ppm (CPy); MS (ESI): m/z (%): 395 (100) [M +H]; HRMS: calcd
+
.87 (s, 3H; 18-H
H; CH O), 3.87 (m, 2H; CH
3
), 2.84 (m, 2H; 6-H
Py), 6.60 (d, J = 2.7 Hz, 1H; 4-H), 6.67
2
), 3.01 (m, 1H; 17b-H), 3.75 (s,
for C33H
55
N
2
O [M +H]: 495.4314; found: 495.4316.
3
3
2
3
3
3
dd, J = 2.7 Hz, J = 8.6 Hz, 1H; 2-H), 7.16 (d, J = 8.6 Hz, 1H; 1-H),
1
3
.25 (m, 2H; 2”H Py), 7.62and 8.52ppm (2m, 2”1H; 2”H
): d = 22.3 (C-18), 23.6 (C-7), 25.8 (C-11), 27.2 (C-16
and C-12), 30.2 (C-6), 33.9 (C-15), 36.5 (C-9), 42.4 (C-8), 48.2 (C-13),
3.0 (CH Py), 55.2(H CO), 66.8 (C-17), 83.7 (C-14), 111.4 (C-2), 113.6
C-4), 122.3 (Cpy-3), 122.5 (CPy-5), 126.5 (C-1), 133.8 (C-10), 136.7 (CPy-4),
38.0 (C-5), 149.2(C Py-2), 157.2 (CPy-6), 158.0 ppm (C-3); MS (ESI): m/z
Py); C NMR
(
62.5 MHz, CDCl
3
Acknowledgement
5
(
1
(
2
3
We gratefully acknowledge financial support from the Deutsche For-
schungsgemeinschaft (Sonderforschungsbereich 436 “Metallvermittelte
Reaktionen nach dem Vorbild der Natur”), the Thuringian Ministerium
für Wissenschaft, Forschung und Kunst, and the Fonds der Chemischen
Industrie. We thank Schering AG for the gift of steroids.
+
+
25 33 2 2
%): 393 (100) [M +H]; HRMS: calcd for C H N O [M +H]:
3
93.2542; found: 393.2535.
1
4a-Hydroxy-17a-amino-3-methoxy-estra-1,3,5(10)-triene (19): Accord-
ing to method A, 17a-AMPY ligand 16 (200 mg, 0.53 mmol) was reacted
I
with Cu (CH
crude product was dissolved in CHCl
3”20 mL). The organic layer was then washed with brine, dried over
Na SO , and concentrated. Separation by preparative TLC with CH Cl
MeOH/NH OH (80:20:0.25) as eluent gave 19 (73 mg, 46%) as a color-
less oil and 17a-amine 15 (45 mg, 30%).
3
CN)
4
PF
6
(240 mg, 0.64 mmol) in acetone (30 mL). The
3
and treated with NH OH (25%)
4
[
1] a) W. Kaim, J. Rall, Angew. Chem. 1996, 108, 47–64; Angew. Chem.
Int. Ed. Engl. 1996, 35, 43–60; b) J. P. Klinman, Chem. Rev. 1996,
(
2
4
2
2
/
9
1
6, 2541–2561; c) M. Pascaly, I. Jolk, B. Krebs, Chem. Unserer Zeit
999, 33, 334–341; d) I. Blain, P. Slama, M. Giorgi, T. Tron, M. Re-
4
glier, J. Biotechnol. 2002, 90, 95–112.
2
D
4
1
1
0
3
8
9: [a] = +68.4 (c = 0.8 in CHCl
3
); H NMR (250 MHz, CDCl
3
): d =
[2] a) N. Kitajima, Y. Moro-Oka, Chem. Rev. 1994, 94, 737–757;
b) K. D. Karlin, S. Kaderli, A. D. Zuberbühler, Acc. Chem. Res.
.81 (s, 3H; 18-H
H; CH O), 6.61 (d, J = 2.7 Hz, 1H; 4-H), 6.70 (dd, J = 2.7 Hz, J =
.6 Hz, 1H; 2-H), 7.20 ppm (d,
): d = 23.9 (C-18), 25.7 (C-7), 26.1 (C-11), 26.5 (C-16),
0.3 (C-12), 30.9 (C-6), 34.3 (C-15), 36.5 (C-9), 42.7 (C-8), 47.2 (C-13),
5.1 (H CO), 59.9 (C-17), 83.9 (C-14), 111.4 (C-2), 113.6 (C-4), 126.4 (C-
), 134.2(C-10), 138.1 (C-5), 157.2ppm (C-3); MS (ESI): m/z (%): 302
3
), 2.84 (m, 2H; 6-H ), 3.26 (m, 1H; 17b-H), 3.76 (s,
2
3
3
3
3
1
997, 30, 139–147; c) R. Than, A. Feldmann, B. Krebs, Coord.
3
13
J
= 8.6 Hz, 1H; 1-H); C NMR
Chem. Rev. 1999, 182, 211–241; d) P. L. Holland, W. P. Tolman,
Coord. Chem. Rev. 1999, 190–192, 855–869; e) S. Schindler, Eur. J.
Inorg. Chem. 2000, 2311–2326; f) A. G. Blackmann, W. P. Tolman,
Struct. Bonding (Berlin) 2000, 97, 179–211; g) I. Blain, M. Giorgi, I.
DeRiggi, M. Reglier, Eur. J. Inorg. Chem. 2001, 205–211; h) L. Que,
Jr., W. B. Tolman, Angew. Chem. 2002, 114, 1160–1185; Angew.
Chem. Int. Ed. 2002, 41, 1114–1137; i) C. Limberg, Angew. Chem.
2003, 115, 6112–6136; Angew. Chem. Int. Ed. 2003, 42, 5932–5954;
j) L. M. Mirica; X. Ottenwaelder, T. D. B. Stack, Chem. Rev. 2004,
1104, 1013–1045; k) E. A. Lewis, W. B. Tolman, Chem. Rev. 2004,
1104, 1047–1076; l) S. Itoh in Comprehensive Coordination Chemis-
try II, Vol. 8, (Eds.: L. Que, Jr., W. B. Tolman, Elsevier, Amsterdam,
2004, pp. 369–-393; m) K. Komiyama, H. Furutachi, S. Nagatomo,
A. Hashimoto, H. Hayashi, S. Fujinami, M. Suzuki, T. Kitagawa,
Bull. Chem. Soc. Jpn. 2004, 77, 59–72.
(
62.5 MHz, CDCl
3
3
5
1
(
3
3
+
+
2
100) [M +H]; HRMS: calcd for C19H29NO [M +H]: 302.2120; found:
02.2124.
1
4a-Hydroxy-16a-(N-2-pyridylmethyl)amino-3-methoxy-estra-1,3,5(10)-
triene (23): According to method A, 16a-AMPY ligand 21 (105 mg,
I
0
0
.28 mmol) was allowed to react with Cu (CH
.34 mmol) in acetone (30 mL). The crude product was dissolved in
(98 mg, 2.6 mmol) was added in small por-
tions. The reaction mixture was stirred at room temperature for 1 h, and
then H O (0.5 mL) was added and the solvent was removed. The residue
was redissolved in CHCl and extracted with NH OH (25%) (4”15 mL).
The organic layer was washed with brine, dried (Na SO ), and concen-
trated. The resulting oily product was separated by column chromatogra-
phy on silica gel eluting with MeOH/CHCl (1:9) to afford 23 (20 mg,
8%) as a light-yellow oil and the reduced ligand 22 (45 mg, 56%).
3
CN)
4
PF
6
(125 mg,
MeOH (15 mL) and NaBH
4
2
3
4
[3] a) K. D. Karlin, J. C. Hayes, Y. Gultneh, R. W. Cruse, J. W.
McKown, J. P. Hutchinson, J. Zubieta, J. Am. Chem. Soc. 1984, 106,
2121–2128; b) O. J. Gelling, F. van Bolhuis, A. Meetsma, B. L. Ferin-
ga, Chem. Commun. 1988, 552–554; c) L. Casella, M. Gullotti, G.
Pallanza, L. Rigoni, J. Am. Chem. Soc. 1988, 110, 4221–4227; d) R.
Menif, A. E. Martell, Chem. Commun. 1989, 1521–1523; e) O. J.
Gelling, B. L. Feringa, J. Am. Chem. Soc. 1990, 112, 7599–7604;
f) R. Menif, A. E. Martell, P. J. Squattrito, A. Clearfield, Inorg.
Chem. 1990, 29, 4723–4729; g) Th. N. Sorrell, V. A. Vankai, M. L.
Garrity, Inorg. Chem. 1991, 30, 207–210; h) T. N. Sorrell, M. L.
Garrity, Inorg. Chem. 1991, 30, 210–215; i) M. Becker, S. Schindler,
R. van Eldik, Inorg. Chem. 1994, 33, 5370–5371; j) S. Ryan, H.
Adams, D. E. Fenton, M. Becker, S. Schindler, Inorg. Chem. 1998,
2
4
3
1
2
D
4
1
2
0
3
(
7
3: [a] = +0.9 (c = 0.7 in MeOH); H NMR (250 MHz, CDCl
3
): d =
.89 (s, 3H; 18-H
H; CH O), 3.90 (m, 2H; CH
3
), 2.84 (m, 2H; 6-H
Py), 6.60 (d, J = 2.7 Hz, 1H; 4-H), 6.69
2
), 3.47 (m, 1H; 16b-H), 3.75 (s,
3
3
2
3
3
3
dd, J = 2.7 Hz, J = 8.6 Hz, 1H; 2-H), 7.16 (d, J = 8.6 Hz, 1H; 1-H),
1
3
.27 (m, 2H; 2”H Py), 7.62and 8.52ppm (2m, 2”1H; 2”H
): d = 23.8 (C-18), 24.1 (CH ), 26.1 (CH
), 36.4 (CH), 40.1 (CH ), 41.0 (CH), 45.5 (CH ), 46.2(C-13),
Py), 55.2(H CO), 55.6 (CH), 83.5 (C-14), 111.4 (C-2), 113.6 (C-
), 122.2 (Cpy-3), 122.5 (CPy-5), 126.6 (C-1), 134.0 (C-10), 136.7 (CPy-4),
38.0 (C-5), 149.2(C Py-2), 157.2 (CPy-6), 158.5 ppm (C-3); MS (ESI): m/z
Py); C NMR
(
62.5 MHz, CDCl
2.0 (CH
2.9 (CH
3
2
2
), 30.1 (CH ),
2
3
5
4
1
(
3
2
2
2
2
3
3
7, 2134–2140; k) M. Becker, S. Schindler, K. D. Karlin, T. A.
Kaden, S. Kaderli, T. Palanche, A. D. Zuberbühler, Inorg. Chem.
999, 38, 1989–1995; l) E. Pidcock, H. V. Obias, C. X. Zhang, K. D.
Karlin, E. I. Solomon, J. Am. Chem. Soc. 1998, 120, 7841–7847;
m) P. L. Holland, K. R. Rodgers, W. B. Tolman, Angew. Chem. 1999,
+
+
25 33 2 2
%): 393 (100) [M +H]; HRMS: calcd for C H N O [M +H]:
1
93.2542; found: 393.2544.
3
3
0
a-(N-2-Pyridylmethyl)amino-5a-hydroxy-cholestane (27): Reaction of
I
a-AMPY ligand 25 (200 mg, 0.42 mmol) with Cu (CH
.5 mmol) in acetone (30 mL) according to method A was followed by re-
(190 mg, 5.0 mmol) in methanol as described for 23
and resulted in an oily product. Preparative TLC eluting with MeOH/
CHCl (1:9) gave 27 (41 mg, 20%) as a colorless oil and 110 mg (55%)
of 3a-(N-2-pyridylmethyl)amino-5a-cholestane 26 (reduced ligand).
3 4 6
CN) PF (190 mg,
1
11, 1210–1213; Angew. Chem. Int. Ed. 1999, 38, 1139–1142; n) L.
Santagostini, M. Gullotti, E. Monzani, L. Casella, R. Dillinger, F.
Tuczek, Chem. Eur. J. 2000, 6, 519–522; o) S. Itoh, H. Kumei, M.
Taki, S. Nagatomo, T. Kitagawa, S. Fukuzumi, J. Am. Chem. Soc.
duction with NaBH
4
3
2
001, 123, 6708–6709.
[
4] a) E. Amadei, E. H. Alilou, F. Eydoux, M. Pierrot, M. Reglier, B.
Waegell, Chem. Commun. 1992, 1782–1784; b) S. Itoh, T. Kondo,
M. Komatsu, Y. Ohshiro, C. Li, N. Kanehisa, Y. Kai, S. Fukuzumi, J.
Am. Chem. Soc. 1995, 117, 4714–4715; c) I. Blain, P. Bruno, M.
Giorgi, E. Lojou, D. Lexa, M. Reglier, Eur. J. Inorg. Chem. 1998,
1297–1304; d) S. Itoh, H. Nakao, L. M. Berreau, T. Kondo, M. Ko-
matsu, S. Fukuzumi, J. Am. Chem. Soc. 1998, 120, 2890–2899; e) S.
Itoh, M. Taki, H. Nakao, P. L. Holland, W. B. Tolman, L. Que, Jr., S.
Fukuzumi, Angew. Chem. 2000, 112, 409–411; Angew. Chem. Int.
Ed. 2000, 39, 398–400; f) P. Spuhler, M. C. Holthausen, Angew.
2
4
1
2
0
3
H
7: [a] = +6.3 (c = 1.6 in CHCl
3
); H NMR (250 MHz, CDCl
), 0.85 (m, 9H; 3”CH ), 0.93 (s, 3H; CH ), 3.05 (m, 1H;
b-H), 3.88 (m, 2H; CH Py), 7.13, 7.23, 7.59, 8.51 ppm (4m, 4”1H; 4”
Py); C NMR (62.5 MHz, CDCl ): d = 12.0 (CH ), 16.0 (CH ), 18.6
), 23.9 (CH
), 34.3 (CH
), 39.9 (C
3
): d =
D
.63 (s, 3H; CH
3
3
3
2
1
3
3
3
3
(
(
(
(
CH
3
2
2
2
), 20.7 (CH
), 25.7 (CH
), 35.1 (CH
), 42.7 (C ), 45.4 (C
), 122.1 (CHPy), 122.6 (CHPy), 136.5 (CHPy), 149.2(CH Py),
2
), 20.9 (CH
), 27.3 (CH
), 35.8 (CH
), 52.5 (CH), 52.9 (CH
2
), 22.5 (CH
3
), 22.7 (CH
3
2
), 24.1
), 35.0
), 40.1
CH
CH
CH
2
2
), 27.9 (C
q
), 28.3 (CH
2
2
2
2
), 36.1 (CH), 39.5 (CH
2
q
q
q
2 2
), 56.1 (CH), 56.3 (CH ),
7
3.9 (C
q
Chem. Eur. J. 2004, 10, 6029 – 6042
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6041

B. Schçnecker et al.
FULL PAPER
Chem. 2003, 115, 6143–6147, Angew. Chem. Int. Ed. 2003, 42, 5961–
[20] M. Dubs, R. Krieg, H. Gçrls, B. Schçnecker, Steroids 2000, 65, 305–
318.
5
965.
[
[
5] J. S. Thompson, J. Am. Chem. Soc. 1984, 106, 8308–8309.
6] I. Blain, M. Giorgi, I. DeRiggi, M. Reglier, Eur. J. Inorg. Chem.
[21] M. Dubs, H. Dieks, W. Günther, M. Kçtteritzsch, W. Poppitz, B.
Schçnecker, Tetrahedron Lett. 2002, 43, 2499–2503.
2
000, 393–398.
[22] M. Gonschior, M. Kçtteritzsch, M. Rost, B. Schçnecker, R. Wyrwa,
Tetrahedron: Asymmetry 2000, 11, 2159–2182.
[23] R. Krieg, R. Wyrwa, U. Mçllmann, H. Gçrls, B. Schçnecker, Steroids
1998, 63, 531–541.
[
7] B. Schçnecker, T. Zheldakova, Y. Liu, M. Kçtteritzsch, W. Günther,
H. Gçrls, Angew. Chem. 2003, 115, 3361–3365; Angew. Chem. Int.
Ed. 2003, 42, 3240–3244.
[
8] A. Magyar, B. Schçnecker, J. Wçlfling, G. Schneider, W. Günther,
H. Gçrls, Tetrahedron: Asymmetry 2003, 14, 1925–1935.
9] H. Arii, Y. Saito, S. Nagatomo, T. Kitagawa, Y. Funahashi, K. Jitsu-
kawa, H. Masuda, Chem. Lett. 2003, 32, 156–157.
[24] E. J. Parish, N. Aksara, T. L. Boos, Lipids 1997, 32, 1325–1330.
[25] É. Frank, E. Mernyµk, J. Wçlfling, G. Schneider, Synlett 2002, 1803–
1806.
[26] a) R. Breslow, J. Yan, S. Belvedere, Tetrahedron Lett. 2002, 43, 363–
365; b) R. Breslow, J. Yang, J. Yan, Tetrahedron 2002, 58, 653–659;
c) J. Yan, R. Breslow, Angew. Chem. 2000, 112, 2804–2806; Angew.
Chem. Int. Ed. 2000, 39, 2692–2694; d) R. Breslow, Z. Fang, Tetrahe-
dron Lett. 2002, 43, 5197–5200.
[
[
[
[
10] A. Magyar, B. Schçnecker, J. Wçlfling, G. Schneider, W. Günther,
H. Gçrls, Tetrahedron: Asymmetry 2003, 14, 2705–2715.
11] V. Amendola, L. Fabrizzi, L. Linati, C. Mangano, P. Pallavicini, V.
Pedrazzini, M. Zema, Chem. Eur. J. 1999, 5, 3679–3688.
12] a) M. Hübner, I. Noack, J. Prakt. Chem. 1972, 314, 667–668; b) K.
Ponsold, M. Hübner, W. Schade, M. Oettel, R. Freund, Pharmazie
[27] COLLECT, Data Collection Software; Nonius B. V., Netherlands,
1998.
1
978, 33, 792–798; c) M. Hübner, K. Ponsold, Z. Chem. 1982, 22,
[28] Z. Otwinowski, W. Minor, “Processing of X-ray Diffraction Data
Collected in Oscillation Mode”, in Methods in Enzymology,
Vol. 276, Macromolecular Crystallography, Part A (Eds.: C. W.
Carter, R. M. Sweet), pp. 307–326, Academic Press 1997.
[29] G. M. Sheldrick, Acta Crystallogr. Sect. A 1990, 46, 467–473.
[30] G. M. Sheldrick, SHELXL-97 (Release 97–2), University of Gçttin-
gen, Germany, 1997.
[31] CCDC-220739 (3), CCDC-220740 (16), and CCDC-220741 (8) con-
tain the supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, U.K.; fax:
(+44)1223-336033; or deposit@ccdc.cam.ac.uk).
1
86.
[
13] a) B. Schçnecker, C. Lange, M. Kçtteritzsch, W. Gçrls, J. Weston, E.
Anders, J. Org. Chem. 2000, 65, 5487–5497; b) C. Herrmann, G.-A.
Hoyer, G. Neef, D. Schomburg, R. Wiechert, Liebigs Ann. Chem.
1
986, 1317–1326; c) F. G. Yaremenko, A. V. Khvat, Mendeleev
Commun. 1994, 187–188 (Chem. Abstr. 1995, 122, 214318w); d) S.
Schwarz, B. Schçnecker, K. Fritsche, A. Poser, C. Lange, W. Günth-
er, St. Gçttke, H. Gçrls, S. Bäsler, Steroids 2003, 68, 113–123; e) E.
Mernyµk, B. Schçnecker, C. Lange, M. Kçtteritzsch, H. Gçrls, J.
Wçlfling, G. Schneider, Steroids 2003, 68, 289–295; f) L. Fielding, Y.
Diepeveen, D. Fletcher, N. Hamilton, Magn. Reson. Chem. 2001, 39,
3
23–328; g) P. Ciuffreda, P. Ferraboschi, E. Verza, A. Manzocchi,
Magn. Reson. Chem. 2001, 39, 648–650; h) J. Wçlfling, É. Frank, E.
Mernyµk, G. Bunkóczi, J. A. Cuesta Seijo, G. Schneider, Tetrahedron
[32] T. Halgren, J. Am. Chem. Soc. 1990, 112, 4710–4723.
[33] M. Bohl, G. Schubert, K. Ponsold, G. Reck, E. Hçhne, K. Simon, J.
Mol. Graphics 1989, 7, 122–129.
[34] W. L. Duax, D. A. Norton, Atlas of Steroid Structure, Vol. I,
Plenum, New York, 1975.
[35] C. Altona, H. J. Geise, C. Romers, Tetrahedron 1968, 24, 13–32.
[36] Cambridge Crystallographic Data Centre, 12Union Road, Cam-
bridge, CB21EZ, UK http://www.ccdc.cam.ac.uk/index.html.
[37] G. de Munno, M. Julve, F. Lloret, J. Faus, M. Verdaguer, Angew.
Chem. 1993, 105, 1122—1124; Angew. Chem. Int. Ed. Engl. 1993, 32,
1046–1048.
2

002, 58, 6851–6861; i) J. Wçlfling, E. Mernyµk, É. Frank, G. Falkay,
. Mµrki, R. Minorics, G. Schneider, Steroids 2003, 68, 277–288;
j) J. Wçlfling, E. Mernyµk, P. Forgó, G. Schneider, Steroids 2003, 68,
51–458; k) E. Mernyµk, J. Wçlfling, G. Bunkóczi, L. Luo, T. R.
Schneider, G. Schneider, Collect. Czech. Chem. Commun. 2003, 68,
141–1148.
4
1
[
14] a) R. Breslow, Acc. Chem. Res. 1980, 13, 170–177; b) R. Breslow,
Chemtracts: Org. Chem. 1988, 333–348.
15] P. A. Grieco, T. L. Stuk, J. Am. Chem. Soc. 1990, 112, 7799–7801.
16] L. Guilan, H. Wenhao, M. Yuzi, J. Yaozhong, Synth. Commun. 1994,
[
[
[38] SYBYL is a registered trademark of Tripos, Inc., 1699 South Hanley
Road, St. Louis, Missouri 63144, USA; http://www.tripos.com.
2
4, 3115–3122.
17] B. Fçhlisch, D. Bakr, P. Fischer, J. Org. Chem. 2002, 67, 3682–3686
Supporting Information).
[
[
[
(
18] S. de la Moya Cerero, A. G. Martínez, E. T. Vilar, A. G. Fraíle, B. L.
Maroto, J. Org. Chem. 2003, 68, 1451–1458.
19] A. G. Martínez, E. T. Vilar, A. G. Fraíle, S. de la Moya Cerero, B. L.
Maroto, Tetrahedron: Asymmetry 2000, 11, 4437–4440.
Received: December 22, 2003
Revised: July 23, 2004
Published online: November 2, 2004
6042
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 6029 – 6042