A bis-steroidal phosphine as new chiral hydrogenation ligand

Full text of DOI:10.1021/jo971444p

7092
J . Org. Chem. 1997, 62, 7092-7093
Sch em e 1
A Bis-Ster oid a l P h osp h in e a s New Ch ir a l
Hyd r ogen a tion Liga n d
V. Enev,1 Ch. L. J . Ewers, M. Harre,
K. Nickisch, and J . T. Mohr*
Process Research, Schering AG-Berlin, Mu¨llerstrasse
170-178, D-13342 Berlin, Germany
Received August 4, 1997
Recently a significant improvement of the BINAP
ligand synthesis was achieved by a nickel-mediated
introduction of the diphenylphosphine residue.2 Yet, the
synthesis of this and similar atropisomeric ligands is still
hampered by the fact that the chirality of the ligand is
obtained from a chiral resolution of a racemic intermedi-
ate late in the synthesis.3 We reasoned that a steroid as
a precursor for an atropisomeric ligand should be attrac-
tive if (i) we could take advantage of the steroid local
chirality for the separation of the ligands and (ii) the
diastereomeric ligands would behave chemically as enan-
tiomers due to the mirror image sterochemistry of the
axis.
In this communication, we describe the synthesis of a
new bis-steroidal phosphine based on the steroidal
precursor equilenine (1), the incorporation of the ligand
into a chiral ruthenium complex, and the first results
from the enantioselective hydrogenation experiments
with this ligand.
properties of the diastereomeric ligands. Therefore, a
Noyori-type asymmetric reduction of acetophenone 4 was
performed with a chiral lithium aluminum hydride
reagent prepared from LiAlH4, ligand 3, and EtOH.9 The
reduction with (R)-3 at -70° C afforded (R)-phenyl
ethanol 5 with an enantiomeric excess of 92.8%. With
ligand (S)-3 it had to be carried out at -50° C due to its
decreased solubility in THF at lower temperature and
afforded (S)-phenyl ethanol 5 with an ee of 63%. At this
point of the investigation we were not interested in the
improvement of the asymmetric reduction of 4. More
important to us was that the opposite absolute configu-
ration of the reduction products confirmed the assign-
ment from CD and proved that both ligands behaved
chemically as enantiomers.
The syntheses of the phosphines (R,S)-7 were ac-
complished according to the protocol for BINAP.2 Ligands
(R,S)-3 were converted into the triflates (R,S)-6 in 90%
yield, which were subsequently treated with diphen-
ylphosphine under nickel catalysis affording ligand (R,S)-7
in 70% yield. The target phosphines (R,S)-7 were thus
available in a short and efficient synthesis from equile-
nine (1) in 58% overall yield (Scheme 1).
Equilenine4 (1) was deoxygenated prior to the coupling
reaction affording desoxy-equilenine 2 in 85% yield
(Scheme 1). While our initial coupling attempts with
Fe3+salts5 failed to give the desired bis-steroid, Mn(acac)3
in acetonitrile at 60 °C afforded the bis-steroids 3 as a
1:1 mixture of diastereomers in 60% combined yield.6 The
yield could further be improved to 96% with Koga’s
copper catalyst at 0 °C.7 The diastereoselectivity of the
coupling showed a moderate temperature dependence
ranging from 1:3 at room temperature to 3:1 at -20 °C.
For practical reasons, the coupling step was usually
carried out at 0 °C, affording a diastereomeric ratio of
1:1.5. As we had hoped, the diastereomeric mixture was
separable by column chromatography and both ligands
displayed mirror image CD spectra. Based on the CD
spectra, the absolute configuration for the major diaste-
reomer was assigned as R and the minor as S.8
Next, we turned our attention to the application of our
ligands (R,S)-7 and decided to investigate the asymmetric
hydrogenation of methyl acetoacetate 8 with RuCl2-
(2) Cai, D.; Payack, J . F.; Verhoeven, T. R. US Patent 5,399,771.
Cai, D.; Payack, J . F.; Bender, D. R.; Hughes, D. L.; Verhoeven, T. R.;
Reider, P. J . J . Org. Chem. 1994, 59, 7180.
(3) Separation of a racemic BIFUB ligand on a chiral stationary
phase was reported: Sirges, W.; Albach, R. W. Proceedings of the Chiral
Europe ′96 Symposium, 14-15 Oct 1996, Strasbourg, France; p 9.
(4) (a) Djerassi, C. J . Am. Chem. Soc. 1950, 72, 4531. Ibid. 4534.
Ibid. 4540. (b) Alder, K.; Schumacher, M. Ann. 1951, 571, 134.
(5) (a) Pummerer, R.; Prell, E.; Rieche, A. Chem. Ber. 1926, 59, 2159.
(b) Toda, F.; Tanaka, K.; Iwata, S. J . Org. Chem. 1989, 54, 3007.
(6) Feringa, B.; Wynberg, H. J . J . Org. Chem. 1981, 46, 2547.
(7) Noji, M.; Nakajima, M. Koga, K. Tetrahedron Lett. 1994, 43,
7983.
(8) (a) IUPAC Tentative Rules for the Nomenclature of Organic
Chemistry. Section E. Fundamental Stereochemistry. In J . Org. Chem.
1970, 35, 2849. (b) Harada, N.; Nakanishi, K. Circular Dichroic
Spectroscopy-Exiton Coupling in Organic Stereochemistry; University
Science Books: Mill Valley, CA, 1983.
While the CD spectra supported our initial assumption
that the chiroptical properties of the ligands are mainly
determined by the bis-steroidal axis, we wanted to
examine whether this also applied to the chemical
* Corresponding author. E-mail: J OERGTORSTEN.MOHR@
SCHERING.DE.
(1) Postdoctoral Fellow on leave from the Bulgarian Academy of
Science, Sofia, Bulgaria.
(9) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J . Am. Chem.
Soc. 1984, 106, 6709.
(10) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Tetrahe-
dron Lett. 1991, 32, 4163.
S0022-3263(97)01444-8 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 21, 1997 7093
(ligand)(DMF)2 910 (eq 1). We were pleased to see that
Ta ble 1. Com p a r ison of Liga n d 7 a n d BINAP
under the described conditions (100 bar, 100 °C, 1 h)
pressure
(atm)
time
(h)
conva
(%)
eeb
(%)
substrate
ligand
s/c
11
11
12
12
BINAP
(R)-7
BINAP
(R)-7
340
605
200
200
7
7
4
4
72
48
24
24
90
>98
44
77c
85.7
87.5d
90.4
>98
a
Determined by NMR analysis of the crude mixture.b Deter-
mined by chiral gas chromatography of the corresponding methyl
ligand (S)-7 turned out to be as active as BINAP. The
diastereomeric ligand (R)-7 afforded (R)-3-hydroxybu-
tanoate with a slightly lower enantiomeric excess of 97%,
confirming again that the diastereomeric ligands induce
enantiomeric sterochemistry in the products.
d
ester. c Best result with ruthenium catalyst: 86% ee.11 est result
with ruthenium catalyst: 91% ee.11
(12), as (R)-7 again afforded (R)-2-methylbutyric acid (14)
with a higher enantiomeric excess. Yet, while our ligand
afforded the product with complete conversion, the BI-
NAP-containing catalyst was less active, affording the
product only with about 40% conversion under these
conditions.
A different set of compounds was thus required to
elucidate possible differences between BINAP and our
ligand. We chose R-acetamidocinnamic acid (11) and
tiglic acid (12) (Table 1) as substrates as there were so
far only moderate ee’s reported for their enantioselective
hydrogenations with BINAP containing chiral ruthenium
or rhodium catalysts.11 Moreover, we decided to apply
the in situ prepared ruthenium catalyst 9 here as well,
because of the appealing simplicity of its preparation. To
the best of our knowledge it is the first time that this in
situ prepared catalyst is applied to the hydrogenation of
alkenes. For simplicity reasons only the results for (R)-7
are shown in Table 1, as the deviation for (S)-7 was in
the range of 1-2% enantiomeric excess for all compounds.
The comparison of our ligand and BINAP showed that
ligand 7 leads to a chiral ruthenium hydrogenation
catalyst of higher activity than the corresponding BINAP-
derived catalyst. The hydrogenation of R-acetamidocin-
namic acid (11) with ligand (R)-7 and BINAP showed an
important difference between both ligands: While similar
conversions were achieved in both reactions, ligand (R)-7
afforded N-acyl-(R)-phenylalanine 13 with a notably
higher enantiomeric excess than BINAP. Moreover, the
hydrogenation with this ligand was faster and required
only half of the amount of the chiral catalyst. A similar
result was achieved in the hydrogenation of tiglic acid
In conclusion, we have presented the short and high-
yielding synthesis of the first representative of a bis-
steroidal phosphine. The results corroborate that both
of our initial criteria are successfully met, as our ligands
turned out to be separable and afforded the formation of
enantiomers in all reactions tested so far. Moreover, the
results from the hydrogenation of R-acetamidocinnamic
acid (11) and tiglic acid (12) show that the new bis-steroid
ligand is in part more active than BINAP and that the
application of the in situ prepared chiral ruthenium
catalyst 9 is not limited to the enantioselective hydro-
genation of â-keto esters. So far, we do not have enough
experimental evidence to explain the difference between
BINAP and our ligand. Further experiments will be
directed to extend the scope of the catalyst application
as well as to investigate structurally modified ligands.
Ack n ow led gm en t . We thank Drs. Depke and
Michl for CD and NMR and F. Igogeit for chiral GC
measurements. Financial support for V.E. by Schering’s
Unternehmenforschungsprogramm is gratefully ac-
knowledged.
Su p p or tin g In for m a tion Ava ila ble: Procedures, analyti-
cal and physical data for compounds 2, 3, 7, and general
procedures for the reduction of compound 4, preparation of
catalyst 9, and hydrogenation of compounds 11 and 12 (6
pages).
(11) (a) Miyashita, A.; Takaya, H.; Souchi, T.; Noyori, R. Tetrahedron
1984, 40, 1245. (b) Ikariya, T.; Ishii, Y.; Kawano, H.; Arai, T.; Saburi,
M.; Yoshikawa, S.; Akutagawa, S. J . Chem. Soc., Chem. Commun.
1985, 922. (c) Ohta, T.; Takaya, H.; Kitamura, M.; Nagai, K.; Noyori,
R. J . Org. Chem. 1987, 52, 3176.
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