Planar - Chiral ferrocenes in asymmetric catalysis: The impact of stereochemically inhomogeneous ligands

Article abstract of DOI:10.1021/ol990683r

(Formula presented) The catalytic properties of stereochemically inhomogeneous mixtures of chiral ferrocenes in dimethylzinc additions to benzaldehyde have been investigated. With planar chiral ferrocene (R_p)-4 a linear correlation between the enantiomeric excess of the ferrocene and that of the product was found. In contrast, a significant departure from linearity was revealed when mixtures of diastereomeric ferrocenes (S,R_p)-1 and (S,S_p)-3 were employed. Thus, even in the reaction with a catalyst obtained from a 1:1 ratio of diastereomers 1 and 3, formation of a product with an enantioselectivity of 95% ee was achieved.

Full text of DOI:10.1021/ol990683r

ORGANIC
LETTERS
1999
Vol. 1, No. 3
491-493
Planar−Chiral Ferrocenes in Asymmetric
Catalysis: The Impact of
Stereochemically Inhomogeneous
Ligands
Carsten Bolm,* Kilian Mun˜iz, and Jens P. Hildebrand
Institut fu¨r Organische Chemie der RWTH Aachen, Professor-Pirlet-Strasse 1,
D-52074 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received May 21, 1999
ABSTRACT
The catalytic properties of stereochemically inhomogeneous mixtures of chiral ferrocenes in dimethylzinc additions to benzaldehyde have
been investigated. With planar chiral ferrocene (R )-4 a linear correlation between the enantiomeric excess of the ferrocene and that of the
p
product was found. In contrast, a significant departure from linearity was revealed when mixtures of diastereomeric ferrocenes (S,R )-1 and
p
(S,S )-3 were employed. Thus, even in the reaction with a catalyst obtained from a 1:1 ratio of diastereomers 1 and 3, formation of a product
p
with an enantioselectivity of 95% ee was achieved.
The stereoselective synthesis of planar-chiral ferrocenes and
their use in asymmetric catalysis has been well-established
over the past years.1 In 1995, Sammakia, Richards, and
Uemura independently reported the preparation of enantio-
pure 2-ferrocenyloxazolines and their diastereoselective ortho
functionalization.2-5 Subsequently, the resulting ferrocenes
were used as chiral ligands in a series of metal-catalyzed
processes.6-11 Within this context, we have recently reported
the synthesis of ferrocenyl hydroxyloxazolines 1-4 (Figure
1).12-14
Studies on the application of these ferrocenes led to a
comprehensive investigation13 of the role of planar chirality
(1) (a) Kagan, H. B.; Riant O. In AdVances in Asymmetric Synthesis;
Hassner, A., Ed.; JAI Press: Greenwich, CT, 1997; Vol. 2, p 189. (b)
Richards, C. J.; Locke, A. J. Tetrahedron: Asymmetry 1998, 9, 2377. (c)
Togni, A. Angew. Chem. 1996, 108, 1581; Angew. Chem., Int. Ed. Engl.
1996, 35, 1475. (d) Ferrocenes; Hayashi, T., Togni, A., Eds.; VCH:
Weinheim, 1995.
(2) (a) Sammakia, T.; Latham, H. A.; Schaad, D. R. J. Org. Chem. 1995,
60, 10. (b) Sammakia, T.; Latham, H. A. J. Org. Chem. 1995, 60, 6002.
Figure 1. Planar chiral ferrocenes.
(c) Sammakia, T.; Latham, H. A. J. Org. Chem. 1996, 61, 1629.
(3) (a) Richards, C. J.; Damalidis, T.; Hibbs, D. E.; Hursthouse, M. B.
Synlett 1995, 74. (b) Richards, C. J.; Mulvaney, A. W. Tetrahedron:
in diethylzinc additions to aldehydes.15 Furthermore, in the
Asymmetry 1996, 7, 1419.
addition to benzaldehyde (5), we found no deviation from
10.1021/ol990683r CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/30/1999

Scheme 1
Table 1. Data for the Asymmetric Methylation of
Benzaldehyde (5) To Give 6 in the Presence of 5 mol % of
Mixtures of 1 and 3
ratio
1:3a
reaction
time (h)
yield of 6
(%)b
ee of 6
(%)c
entry
1
2
3
4
5
6
7
8
9
100:0
88:12
67:33
50:50
43:57
35:65
26:74
13:87
6:94
6
12
12
12
14
11
13
15
12
12
14
99
99
97
98
89
69
74
71
36
22
17
97
96
95
94
91
90
88
79
20
linearity (nonlinear effect, NLE16) between the enantiomeric
excesses of the ferrocene and the product alcohol13 by using
mixtures of enantiomers of 2, which is a ferrocene with both
a stereogenic center and a plane of chirality. The same linear
relationship was now revealed in catalyzed additions of
dimethylzinc to benzaldehyde in the presence of ferrocene
(Rp)-4 which displays planar chirality only (Scheme 1, Figure
2).
10
11
2:98
0:100
-32
-50
a Determined by 1H NMR. b After column chromatography. c Determined
by HPLC using a Chiralcel OD column.
wondered about the catalytic properties of mixtures of
diastereomeric ferrocenes. These results are of particular
interest in cases where the initial ortho functionalization,
which is used in the synthesis of ferrocene ligands such as
1, does not occur in a highly stereoselective manner. A
mixture of diastereomers is then obtained, and a separation
is required to isolate each diastereomeric product in stereo-
chemically homogeneous form. However, if these mixtures
of diastereomers themselves could efficiently be used in the
catalysis, this additional separation step would become
unnecessary and the overall process would be simplified.
We therefore decided to study the intentional application
of non-diastereomerically pure planar-chiral ligands in
asymmetric catalysis using nonequal mixtures of diastereo-
meric ferrocenes 1 and 3 in enantioselective dimethylzinc
additions to benzaldehyde (5) as model system. The results
for catalyses with 5 mol % of ferrocenes are given in Table
1 and are depicted as graphical representation in Figure 3.
Figure 2.
In both of these amplification studies, nonequal mixtures
of enantiomeric ferrocenes were employed, and we now
(4) (a) Nishibayashi, Y.; Uemura, S. Synlett 1995, 79. (b) Nishibayashi,
Y.; Segawa, K.; Arikawa, Y.; Ohe, K.; Hidai, M.; Uemura, S. J. Organomet.
Chem. 1997, 545-546, 381.
(5) See also: Ahn, K. H.; Cho, C.-W.; Baek, H.-H.; Park, J.; Lee, S. J.
Org. Chem. 1996, 61, 4937.
(6) Hydrosilylation: (a) Nishibayashi, Y.; Segawa, K.; Ohe, K.; Uemura,
S. Organometallics 1995, 14, 5486. (b) Nishibayashi, Y.; Segawa, K.;
Takada, H.; Ohe, K.; Uemura, S. Chem. Commun. 1996, 847.
(7) Transfer hydrogenation: (a) Sammakia, T.; Stangeland, E. L. J. Org.
Chem. 1997, 62, 6104. (b) Nishibayashi, Y.; Takei, I.; Uemura, S.; Hidai,
M. Organometallics 1998, 17, 3420. (c) Arikawa, Y.; Ueoka, M.; Matoba,
K.; Nishibayashi, Y.; Hidai, M.; Uemura, S. J. Organomet. Chem. 1999,
572, 163.
(8) Allylic substitution: (a) Ahn, K. H.; Cho, C.-W.; Park, J.; Lee, S.
Tetrahedron: Asymmetry 1997, 8, 1179. (b) Ahn, K. H.; Cho, C.-W.; Park,
J.; Lee, S. Bull. Korean Chem. Soc. 1997, 18, 789. (c) For the importance
of planar chirality in this reaction, see: You, S.-L.; Zhou, Y.-G.; Dai,
L.-X. Chem. Commun. 1998, 2765.
(9) Michael addition: Stangeland, E. L.; Sammakia, T. Tetrahedron 1997,
53, 16503.
(10) Grignard cross-coupling: Richards, C. J.; Hibbs, D. E.; Hursthouse,
M. B. Tetrahedron Lett. 1995, 36, 3745.
(11) Asymmetric rearrangement of allylic imidates: Donde, Y.; Overman,
L. E. J. Am. Chem. Soc. 1999, 121, 2933.
(12) Bolm, C.; Mun˜iz-Ferna´ndez, K.; Seger, A.; Raabe, G. Synlett 1997,
1051.
Figure 3.
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Org. Lett., Vol. 1, No. 3, 1999

A very pronounced nonlinear relationship between the ee
of product 6 and the de of the ferrocenesadjusted by mixing
of appropriate amounts of (S,Rp)-1 and (S,Sp)-3swas ob-
served. The highest enantiomeric excess for 6 was obtained
in a catalysis with diastereomerically pure (S,Rp)-1 (Table
1, entry 1). Interestingly however, decreasing the de of the
ferrocene had only a minor impact on the ee of the product.
Thus, even with a 1:1 mixture of diastereomeric ferrocenes
(S,Rp)-1 and (S,Sp)-3 (entry 4), the enantiomeric excess of 6
was still 94%. Moreover, with an increased catalyst loading
of 10 mol %, complete conversion of 5 was observed and
product 6 had 96% ee!
Since we found no indication for the formation of higher
aggregates in catalyses with ferrocenes 2 and 4 and since
the rate of the methyl transfer was almost independent of
the composition of the ligand mixture (entries 1-8), we
conclude that the present nonlinear effect (NLE) is not a
consequence of the formation of catalytically inactive
aggregates.17,18 Instead, we understand that it is a result of
drastically different rates19 of the two diastereomeric catalysts
derived from 1 and 3.
mixtures of diastereomeric DAIBs with opposite chirality
led to a significant decrease in reaction rate.
To the best of our knowledge, there is only one other
example of a NLE based on the use of catalysts with two
kinetically competing nonenantiomeric ligands. In 1995,
Kagan described osmium-catalyzed AD reactions in the
presence of cinchona alkaloid mixtures.21 A strong nonlinear
relationship between the ee of the product and the (formal)
de of the ligand was revealed. In this case, however, the
ligands did not have a diastereomeric relationship, but instead
they were distinctly different in structure.22
In summary, we have shown that asymmetric catalysis
does not necessarily require the use of diastereomerically
pure ligands for achieving high enantioselectivities. If the
diastereomeric catalysts operate on significantly different
rates, even a ligand with a small de can give a product with
high ee. This principle could be of general preparative
importance in those cases where no complete stereoselectivity
in a ligand functionalization process is feasible.4b,6,23 In the
present context, it is important to realize that the diastereo-
meric mixture of 1 and 3 formally represents the product of
an unselectiVe ortho functionalization of a chiral 2-ferro-
cenyloxazoline. Thus, even if this functionalization process
was not stereoselective, the resulting diastereomeric mixture
as such could also be highly useful in enantioselective
catalysis.
This assumption is also substantiated by the observation
that reactions with ferrocene mixtures in which 3 is the major
component give product 6 of R configuration (entries 5-9).
In contrast, S-configurated 6 is obtained with diastereomeri-
cally pure ferrocene 3 (entry 11).
It is noteworthy that in a related investigation, Noyori
observed significantly different selectivity profiles when
diastereomeric isoborneol-based amino alcohols such as
DAIB were used in the asymmetric addition of diethylzinc
to benzaldehyde.20 In this case, due to the high reactivity of
each diastereomeric catalyst and the existence of heterochiral
aggregates the nonlinear behavior was completely dominated
by the stereoisomer in excess. In addition, use of equimolar
Acknowledgment. We are grateful to the Deutsche
Forschungsgemeinschaft (DFG) within the Collaborative
Research Center (SFB) 380 “Asymmetric Synthesis by
Chemical and Biological Methods” and the Fonds der
Chemischen Industrie for financial support. We thank Dr.
K. Gu¨nther at DEGUSSA-HU¨ LS AG, Hanau/Germany, for
preparative HPLC separation of ferrocene 4 and J. Rudolph
for assistance with the preparation of the graphical figures.
Supporting Information Available: General procedures
for dimethylzinc addition to benzaldehyde, results of cataly-
ses as detailed in Figure 2, HPLC separation conditions for
ferrocene 4, and spectral reproduction of a mixture of
diastereomeric ferrocenes 1 and 3. This material is available
free of charge via the Internet at http://pubs.acs.org.
(13) Bolm, C.; Mun˜iz-Ferna´ndez, K.; Seger, A.; Raabe, G.; Gu¨nther, K.
J. Org. Chem. 1998, 63, 7860.
(14) Mun˜iz-Ferna´ndez, K. Ph.D. Thesis, RWTH Aachen 1998.
(15) (a) Noyori, R.; Kitamura, M. Angew. Chem. 1991, 102, 34; Angew.
Chem., Int. Ed. Engl. 1991, 30, 49. (b) Soai, K.; Niwa, S. Chem. ReV. 1992,
92, 833.
(16) (a) Girard, C.; Kagan, H. B. Angew. Chem. 1998, 110, 3088; Angew.
Chem., Int. Ed. Engl. 1998, 37, 2922. (b) Bolm, C. In AVanced Asymmetric
Synthesis; Stephenson, R., Ed.; Capman and Hall: London, 1996; p 9. (c)
Avalos, M.; Babiano, R.; Ciutas, P.; Jime´nez, J. L.; Palacios, J. C.
Tetrahedron: Asymmetry 1997, 8, 2997.
OL990683R
(17) Kitamura, M.; Yamakawa, M.; Oka, H.; Suga, H.; Noyori, R. Chem.
Eur. J. 1996, 2, 1173 and references therein.
(21) Zhang, S. Y.; Girard, C.; Kagan, H. B. Tetrahedron: Asymmetry
1995, 6, 2637.
(22) For other related investigations on diastereomeric catalyst mixtures
see: (a) Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1993, 115, 12579. (b)
Giardello, M. A.; Conticello, V. P.; Brard, L.; Gagne´, M. R.; Marks, T. J.
J. Am. Chem. Soc. 1994, 116, 10241. (c) Fu, P.-F.; Brard, L.; Li, Y.; Marks,
T. J. J. Am. Chem. Soc. 1995, 117, 7157.
(23) For a recent report of an unselective ortho functionalization on
2-cymantrenyloxazolines, see: Kudis, S.; Helmchen, G. Angew. Chem. 1998,
110, 3210; Angew. Chem., Int. Ed. Engl. 1998, 37, 3047.
(18) To date, there is only one report on a NLE for a ferrocene ligand
in an asymmetric diethylzinc addition: Nicolosi, G.; Patti, A.; Morrone,
R.; Piattelli, M. Tetrahedron: Asymmetry 1994, 5, 1639.
(19) For kinetic implication of nonlinear effects see: (a) Blackmond,
D. G. J. Am. Chem. Soc. 1998, 120, 13349. (b) Blackmond, D. G., J. Am.
Chem. Soc. 1997, 119, 12934.
(20) (a) Kitamura, M.; Suga, S.; Niwa, M.; Noyori, R. J. Am. Chem.
Soc. 1995, 117, 4832.
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