O-Silylated steroidal cis-aminoalcohols as chiral auxiliaries: Highly diastereoselective Pd-catalyzed cyclopropanation of α,β-unsaturated aldimines

Article abstract of DOI:10.1016/S0040-4039(02)00334-9

α,β-Unsaturated imines, obtained from cis-17-silyloxy-16-amino steroids and α,β-unsaturated aldehydes, react with diazomethane in the presence of a catalytic amount of Pd(OAc)₂ with high chemo- and diastereoselectivities to form steroidal cyclo

Full text of DOI:10.1016/S0040-4039(02)00334-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2499–2503
O-Silylated steroidal cis-aminoalcohols as chiral auxiliaries:
highly diastereoselective Pd-catalyzed cyclopropanation of
a,b-unsaturated aldimines†
M. Dubs,a H. Dieks,a W. Gu¨nther,a M. Ko¨tteritzsch,a W. Poppitzb and B. Scho¨neckera,*
aInstitut fu¨r Organische Chemie und Makromolekulare Chemie, Friedrich-Schiller-Universita¨t Jena, Humboldtstr. 10,
D-07743 Jena, Germany
bInstitut fu¨r Anorganische und Analytische Chemie, Friedrich-Schiller-Universita¨t Jena, Humboldtstr. 10, D-07743 Jena, Germany
Received 15 February 2002; accepted 16 February 2002
Abstract—a,b-Unsaturated imines, obtained from cis-17-silyloxy-16-amino steroids and a,b-unsaturated aldehydes, react with
diazomethane in the presence of a catalytic amount of Pd(OAc)2 with high chemo- and diastereoselectivities to form steroidal
cyclopropanocarbaldimines; chromatography on silica gel gives the substituted cyclopropanocarbaldehydes with a high enan-
tiomeric excess and allows recovery of the chiral steroidal auxiliaries. © 2002 Elsevier Science Ltd. All rights reserved.
Steroids have a great unexplored potential as chiral
auxiliaries and chiral ligands, which has previously been
demonstrated for only a few examples.1,2 In connection
with our investigations employing differently substi-
tuted chiral steroids with different configurations as
model compounds in stereoselective synthesis,2 we
became interested in using these compounds as chiral
auxiliaries for the cyclopropanation of cinnamic acid
and cinnamic aldehyde derivatives. In particular, we
Pd-catalyzed cyclopropanation.5 Simple procedures
using chiral auxiliaries should therefore be useful to
obtain the desired cyclopropanes. An advantage of this
method is the synthesis of only cis- or trans-1,2-disub-
stituted cyclopropanes depending on wether the cis- or
trans-olefin is employed, whereas the cyclopropanation
of simple olefins with diazoesters normally gives a
mixture of cis- and trans-1,2-disubstituted cyclo-
propanes. Two kinds of chiral auxiliaries are described
for the Pd-catalyzed cyclopropanation of trans-
olefins.6,7 (−)-Ephedrine was reacted with (E)-cinnamic
aldehyde to give an oxazolidine. Cyclopropanation of
the double bond proceeded with high diastereoselectiv-
ity and the subsequent hydrolysis gave the trans-
phenyl-cyclopropanecarbaldehyde with the 1R,2R-
configuration.6 For the success of this method, it is
necessary to create the new stereocenter in the oxazo-
lidine ring with high stereoselectivity.6 The other
method started with Oppolzer’s sultam. After synthesis
of the sultams of (E)-a,b-unsaturated carboxylic acids
in a two-step sequence, cyclopropanation of the prod-
ucts with diazomethane gave the expected cyclo-
propanes with good diastereoselectivies. Cleavage under
relatively drastic conditions furnished the desired
homochiral trans-substituted cyclopropanecarboxylic
acids.7
employ
D-ring substituted 3-methoxy-estra-1,3,5(10)-
trienes because of the well-defined and restricted con-
formation of the anellated cyclopentane ring.2
Chiral 1,2-disubstituted cyclopropanes are important
natural products and synthetic compounds which pos-
sess biological activities.3 One way to synthesize substi-
tuted cyclopropanes is the Pd-catalyzed reaction of
substituted olefins with diazomethane.4 In contrast to
the well-known enantioselective copper- or rhodium-
catalyzed addition of diazoesters to simple olefins,4 the
former reaction seems to be unsuccessful as an enan-
tioselective route using chiral ligands. In a careful study
of Denmark and co-workers on this reaction, only
racemates were obtained in the chiral ligand mediated
Keywords: steroids; aminoalcohols; catalysis; cyclopropanes; stereo-
chemistry.
We synthesized a number of cinnamic esters of the 17b-
and 17a-alcohols of the estratriene series8 that also
contain neighboring groups in the 16-position for the
Pd-catalyzed cyclopropanation reaction with di-
* Corresponding author. Tel.: 03641 948225; fax: 03641 948292;
e-mail: c8scbr@uni-jena.de
†
Dedicated to Professor E.-G. Ja¨ger on the occasion of his 65th
birthday.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00334-9

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M. Dubs et al. / Tetrahedron Letters 43 (2002) 2499–2503
azomethane. In all cases, only low diastereoselectivies
could be observed. Recently, we described the conden-
sation products of (E)-cinnamic aldehydes with primary
17- and 16-amines and aminoalcohols of steroids.2a
These chiral a,b-unsaturated imines can be transformed
into planar-chiral stable (1-azadiene)Fe(CO)3 com-
plexes and to 1,3-dihydro-pyrrol-2-ones, in some cases
with high diastereoselectivies.2a,d Surprisingly, the reac-
tion of a,b-unsaturated aldimines with diazomethane
has not yet been described. Only the cyclopropanation
of such compounds with a phenylchromium Fischer
carbene complex has been reported.9 No face discrimi-
nation has been observed for the reaction of the azadi-
CDCl3; l [ppm]=1.51, m, 1H; 1.70, m, 1H; 2.15, m,
1H; 2.60, m, 1H; 7.09–7.30, m, 5H; 9.31, d, J=4.57 Hz,
1H) was obtained in a yield higher than 80% as well as
1
the steroid amine ligand 1 (90%). H NMR shift exper-
iments employing (S)-2,2,2-trifluoro-1-(9-anthranyl)-
ethanol were successful in differentiating the signals of
the enantiomers 5 and 6, especially for the aldehydic
proton. We could observe two doublets in a ratio of
nearly 1:1. However, an exact determination of the
ratio was impossible because a large amount of the shift
reagent was necessary for differentiation.
A similar stereochemical result has been obtained by
cyclopropanation of the imine 10 synthesized from the
16b,17b-aminoalcohol 72a (Schemes 2 and 3) (15a and
15b) although 10 reacted to only one diastereomeric
Fe(CO)3 complex.2a We therefore synthesized the 17b-
(tert-butyl-diphenyl)silyloxy-16b-cinnamic aldimine 11
from 7 (Scheme 2) for cyclopropanation experiments.
In this compound, one face of the unsaturated imine
should be blocked by the 13b-methyl- and the 17b-
silyloxy group.
ene
obtained
from
(+)-Ph(Me)CHNH2
and
(E)-cinnamic aldehyde.9 Therefore, we have investi-
gated the reactions of steroidal a, b-unsaturated imines
with diazomethane for their chemo- and stereoselectivi-
ties. Our first attempt with the (E,E)-azadiene 2,
[obtained from the 17b-amine 1 and (E)-cinnamic
aldehyde2a] Pd(OAc)2 and diazomethane proceeded
with high chemoselectivity at the CꢀC double bond
(Scheme 1).
In a smooth reaction, a mixture of the diastereomeric
The 1H NMR spectrum of the cyclopropanation
product pointed to two diastereomers (16a and 16b),
with one diastereomer dominating (two NꢀCꢁH signals
in a ratio of 98.5:1.5, l=6.31 and 6.39 ppm; selective
TOCSY to the cyclopropane proton signals). The trans-
phenyl-cyclopropanocarbaldehyde, obtained after chro-
matography in a high yield in addition to the chiral
auxiliary 8, was determined as a mixture of the two
enantiomers 5 and 6 by 1H NMR spectroscopy employ-
ing the chiral shift reagent (two doublets of the alde-
hyde proton signal with strong different intensity). An
exact determination of the ratio could be achieved by
GC with a chiral column (CP 9000, Chirasil-Dex CB,
DF=0.25mm, l=25 m, ¥=0.25 mm; 120°C, isother-
trans-substituted cyclopropanes 3 and 4 could be iso-
1
lated in a high yield. Detailed H NMR analysis (400
MHz, CDCl3; two signals for the angular 13b-methyl
group, l=0.801 and 0.825 ppm, ratio 54:46; TOCSY
experiments for the cyclopropane protons show signal
doubling) pointed to a low diastereoselectivity with a
nearly 1:1 ratio for the diastereomeric steroidal cyclo-
propanes. After hydrolysis of the diasteromeric
steroidal aldimines 3 and 4 by a simple chromatogra-
phy on silica gel (Fa. Merck, 0.04–0.06 mm, elution
with CH2Cl2/CH3OH 20:1), a mixture of the enan-
tiomeric (1S,2S)- and (1R,2R)-trans-phenyl-cyclo-
propanocarbaldehydes 5 and 6 (1H NMR, 400 MHz,
Scheme 1. Cyclopropanation of cinnamic aldimine from the 17b-amine. Reagents and conditions: (i) cinnamic aldehyde/CH3OH,
rt; (ii) CH2Cl2, Pd(OAc)2, CH2N2/ether, −10°C to rt, 18 h; (iii) silica gel, elution with CH2Cl2/CH3OH 20:1 and CH3OH.

M. Dubs et al. / Tetrahedron Letters 43 (2002) 2499–2503
2501
Scheme 2. Cyclopropanation of cinnamic aldimines from the 16,17-cis-aminoalcohols and O-silylated derivatives. Reagents and
t
conditions: (i) CH2Cl2/ClSiPh2 Bu, 4-N,N-dimethyl-aminopyridine, triethylamine, rt, 4 days; (ii) cinnamic aldehyde/CH3OH, rt, 5
h; (iii) CH2Cl2, Pd(OAc)2 (3–5 mol%), CH2N2/ether, −10°C to rt, 18 h.
Scheme 3. Hydrolysis of steroidal cyclopropano imines. Stereochemical outcome. Reagents and conditions: chromatography at
silica gel with CH2Cl2/CH3OH (20:1) and CH3OH.

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M. Dubs et al. / Tetrahedron Letters 43 (2002) 2499–2503
mic). The ratio of the two peaks was 98.6:1.4 (lower
retention time) in very good agreement with the ratio
given by the NMR method.
rated aldimines with diazomethane leads to cyclo-
propanocarbaldimines. Using diastereomeric steroidal
cis-17-silyloxy-16-cinnamic aldimines, high diasterose-
lectivities of the cyclopropanation reaction could be
observed. Simple chromatography gave the enan-
tiomeric trans-phenyl-cyclopropanocarbaldehydes with
high enantiomeric excess and the steroidal chiral auxil-
iaries. The steroidal cis-aminoalcohols are available
from 3-O-methylestrone, a pharmaceutical.10
The absolute configuration of the enantiomer (ee=
97%) is 1S,2S as could be determined from the high
positive optical rotation as compared to the reported
high negative value for the 1R,2R configuration ([h]D
−340, CHCl3).6 The GC determination of the ratios for
the two enantiomeric aldehydes 5 and 6, synthesized
from the 17-imino compounds 2 and 10, gave values of
55.3:44.7 and 54.6:46.4, respectively (Scheme 3).
Acknowledgements
In order to determine the stereochemical outcome of
the cyclopropanation reaction with the opposite
configuration at C17 and C16, we synthesized the 17a-
(tert-butyl-diphenyl)silyloxy-16a-cinnamic aldimine 12
from the 17a,16a-aminoalcohol10 by silylation (9) and
condensation (12). The cyclopropanation products
from 1211 (Scheme 2 17a and 17b) were investigated by
1H NMR spectroscopy. Two signals for the angular
13b-methyl group (l=0.644 and 0.614 ppm) in a ratio
of 95:5 pointed to a high excess of one diastereomer.
After chromatography, the mixture of the enantiomeric
cyclopropanes 5 and 6 and the chiral auxiliary 9 could
be obtained in high yields. The ratio of the enantiomers
6 and 5, determined by GC, was 95.1:4.9 (higher reten-
tion time), which is again in very good agreement with
the NMR method (Scheme 3). The high enantiomeric
excess (ee>90%) of 6 with the (1R,2R) configuration,
obtained from the 17a,16a-configurated steroid 12, is
remarkable and demonstrates that the other asymmet-
ric centers of the steroid core are not determining the
stereochemistry of the cyclopropanation reaction. The
stereochemical outcome of the cyclopropanation is in
good agreement with our stereochemical model for
imines which includes a preferred conformation with a
small torsional angle 16HꢁC16ꢁNꢀC2a,b and a transoid
arrangement of the unsaturated imino group, also
confirmed by an X-ray analysis of 12.
We thankfully acknowledge financial support from the
Deutsche Forschungsgemeinschaft, Sonderforschungs-
bereich 436 and the Fonds der Chemischen Industrie.
We thank Schering AG for the gift of 3-O-
methylestrone and S. Go¨ttke for experimental
assistance.
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This reaction is also useful for the synthesis of cyclo-
propanes with a new quaternary chiral center as we
could demonstrate with the reaction at the compounds
13 and 14, obtained by condensation of the O-silylated
aminoalcohols 8 and 9 with (E)-a-methylcinnamalde-
hyde (Scheme 2). After hydrolysis of the steroidal
cyclopropanes 18 and 19 94.2:5.8 and 20.0:80.0 mix-
tures of the enantiomeric cyclopropano aldehydes 20
and 21 (ee=88.4 and 60.0%) could be obtained
(Scheme 3). Also, in these cases the auxiliaries could be
recovered easily and in high yields.
Using (1S,2R)-cis-1-amino-2-hydroxyindane (Aldrich)
for the described procedure (O-silylation, condensation
with cinnamic aldehyde, cyclopropanation, hydrolysis)
gave 5 and 6 in a ratio of 74:26 (ee=48%). A further
disadvantage are the oily products in this series in con-
trast to the crystalline steroid compounds, which can be
easily recovered.
3. Salau¨n, J. Topics Curr. Chem. 2000, 207, 1–67.
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York, Chichester, Brisbane, Singapore, Toronto, 1998;
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In summary, we have demonstrated for the first time
that the Pd-catalyzed cyclopropanation of a,b-unsatu-
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18 h at rt, the mixture was filtered and the solvents
were evaporated in vacuo. The solid residue [660 mg,
98.8%, diastereomeric mixture of 17a and 17b, ratio
5:95, 1H NMR: CDCl3, l [ppm]: 0.614 and 0.644 (2×s,
3H, 18H3, 5:95)] was hydrolyzed by column chromatog-
raphy on silica gel with CH2Cl2/CH3OH (20:1) and
CH3OH; fraction 1: trans-2-phenyl-cyclopropano-1-car-
baldehyde as an oil (120 mg, 82%, mixture of the enan-
tiomers 5 and 6, ratio 4.9:95.1, determined by GC with
a chiral column Chirasil-Dex CB, 120°C, isothermic,
minor component 5 with higher retention time). 1H
NMR: CDCl3, l [ppm]: 1.51, m, 1H; 1.70, m, 1H; 2.15,
m, 1H; 2.60, m, 1H; 7.09–7.30, m, 5H, arom. H; 9.31,
d, J=4.57 Hz, aldehyde H; fraction 2: O-silylated
steroidal aminoalcohol 9 (490 mg, 90.8%, white foam).
8. All new steroidal compounds were characterized by ele-
1
mental analysis, [h]D, and H NMR spectra. Details will
be reported later in a full paper.
9. Barluenga, J.; Toma´s, M.; Lo´pez-Pelegrin, J. A.; Rubio,
E. J. Chem. Soc., Chem. Commun. 1995, 665–666.
10. Scho¨necker, B.; Ponsold, K. Tetrahedron 1975, 31,
1113–1118.
11. Procedure for the cyclopropanation: A stirred solution
of the steroid imine 12 (654 mg, 1.0 mmol) in dry
CH2Cl2 (20 ml) was treated at −10°C with Pd(OAc)2
(6.7 mg, 30 mmol) and an etheral solution of dia-
zomethane (15 ml, 7.5 mmol CH2N2, prepared from
N-methyl-N%-nitro-N-nitroso guanidine, Fluka). After
1H NMR: identical with
9 synthesized from the
16a,17a-amino alcohol.10