First examples of improved catalytic asymmetric C-C bond formation using the monodentate ligand combination approach

Article abstract of DOI:10.1021/ol035106o

(Matrix presented) Using a combination of chiral monodentate phosphoramidite ligands in the rhodium-catalyzed conjugate addition of boronic acids to three different substrates, we have shown for the first time that the ligand combination approach is applicable for C-C bond formation. Chiral catalysts based on hetero-combinations of ligands are found to be more effective than the homo-combinations, ³¹P NMR experiments show that the hetero-combinations are formed in excess over the homo-combinations.

Full text of DOI:10.1021/ol035106o

ORGANIC
LETTERS
2003
Vol. 5, No. 17
3111-3113
First Examples of Improved Catalytic
Asymmetric C−C Bond Formation Using
the Monodentate Ligand Combination
Approach
Ate Duursma, Rob Hoen, Julia Schuppan, Ron Hulst, Adriaan J. Minnaard,* and
Ben L. Feringa*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute,
UniVersity of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
b.l.feringa@chem.rug.nl
Received June 17, 2003
ABSTRACT
Using a combination of chiral monodentate phosphoramidite ligands in the rhodium-catalyzed conjugate addition of boronic acids to three
different substrates, we have shown for the first time that the ligand combination approach is applicable for C−C bond formation. Chiral
catalysts based on hetero-combinations of ligands are found to be more effective than the homo-combinations. 31P NMR experiments show
that the hetero-combinations are formed in excess over the homo-combinations.
The asymmetric rhodium-catalyzed conjugate addition of
boronic acids, developed by Miyaura and Hayashi,1 is a
highly convenient method for introducing an sp2-sp3 C-C
bond with simultaneous formation of a new stereogenic
center. The reaction is applicable to a broad range of sub-
strates such as enones,1c R,â-unsaturated esters,2 R,â-un-
saturated amides,3 1-alkenylphosphonates,4 and 1-nitroal-
kenes.5 Excellent levels of enantioselectivity have been
reached using BINAP,1 phosphonites,6 and amidophosphines7
as chiral ligands. We have recently shown that chiral
monodentate phosphoramidites are versatile ligands for this
reaction,8 thereby introducing a class of cheap and easily
tunable ligands that have already proven to be highly
successful in the copper-catalyzed asymmetric conjugate
addition of diorganozinc reagents9 and rhodium-catalyzed
asymmetric hydrogenations.10 The monodentate nature of
these phosphoramidite ligands allows us to apply the recently
(1) (a) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16,
4229-4231. (b) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Saskai, M.;
Miyaura, N. J. Am. Chem. Soc. 1998, 120, 5579-5580. (c) Hayashi, T.
Synlett 2001, 879-887. (d) Hayashi, T.; Takahashi, M.; Takaya, Y.;
Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052-5058.
(2) (a) Takaya, Y.; Senda, T.; Kurushima, H.; Ogasawara, M.; Hayashi,
T. Tetrahedron: Asymmetry 1999, 10, 4047-4056. (b) Sakuma, S.; Sakai,
M.; Itooka, R.; Miyaura, N. J. Org. Chem. 2000, 65, 5951-5955.
(3) (a) Senda, T.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 2001, 66,
6852-6856. (b) Sakuma, S.; Miyaura, N. J. Org. Chem. 2001, 66, 8944-
8946.
(5) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122,
10716-10717.
(6) Reetz, M. T.; Moulin, D.; Gosberg, A. Org. Lett. 2001, 3, 4083-
4085.
(7) Kuriyama, M.; Nagai, K.; Yamada, K.; Miwa, Y.; Taga, T.; Tomioka,
K. J. Am. Chem. Soc. 2002, 124, 8932-8939.
(8) Boiteau, J. G.; Imbos, R.; Minnaard, A. J.; Feringa, B. L. Org. Lett.
2003, 5, 681-684. See also: Boiteau, J. G.; Imbos, R.; Minnaard, A. J.;
Feringa, B. L. Org. Lett. 2003, 5, 1385.
(4) Hayashi, T.; Senda, T.; Takaya, Y.; Ogasawara, M. J. Am. Chem.
Soc. 1999, 121, 11591-11592.
10.1021/ol035106o CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/22/2003

introduced ligand combination approach in asymmetric
catalysis.11 Since the catalytically active species contains two
monodentate ligands, a mixture of two different phosphora-
midites (Lx and Ly) will lead to the formation of two homo-
complexes, Rh(Lx)2 and Rh(Ly)2, and the hetero-complex
Rh(LxLy) simultaneously.12 The hetero-complex represents
a new catalyst, and if it shows higher activity and selectivity
than the two homo-complexes simultaneously present in the
reaction mixture, it will not only lead to better results but
offer an easy combinatorial method for screening for effective
chiral catalysts. This principle has been successful for
asymmetric hydrogenations but so far has not been demon-
strated for asymmetric C-C bond formation (Figure 1).11
Scheme 1. Conjugate Addition to 4-Methyl-nitrostyrene
Figure 1. Rh complexes with two monodentate ligands using the
ligand combination approach.
the configuration also plays a role because a strong mis-
matched effect is found when ent-L3 is used in combination
with L1 (18% conversion, -23% ee).
On the basis of these encouraging preliminary results, the
use of ligand combinations in arylboronic acid addition to
enones was investigated. Benzylidene acetone (3) was
considered to be an attractive substrate (Scheme 2). â-Aryl-
As the first substrate, we used 4-methyl-nitrostyrene (1)
(Scheme 1), a nitroalkene lacking R-substituents, which has
until now resisted a highly enantioselective conjugate addi-
tion of boronic acids and is therefore a good candidate for
the mixed ligand approach.
The reaction conditions have been slightly modified with
respect to those in previous reports on the arylboronic acid
coupling.5,8 Since it was found that large amounts of water
can lead to catalyst deactivation, arylboroxines in combina-
tion with 1 equiv of water with respect to boron were used,4
leading to in situ arylboronic acid formation. From the data
in Scheme 1, it follows that for homo-combinations of chiral
ligands L1-L3, with an increase of steric bulk going from
L1 to L3, the conversion decreases but the enantioselectivity
increases. Making hetero-combinations of a bulky ligand (L2
or L3) and the relatively small L1 combines the best
properties of both ligands. With the hetero-combination
L1/L2, a higher conversion as well as a higher ee is obtained
compared to their homo-combinations. For the other two
combinations, the effect on the enantioselectivity is even
stronger. Not only the small size of L1 is important,13 but
Scheme 2. Conjugate Addition to Benzylidene Acetone
(9) (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346-353. (b) Naasz,
R.; Arnold, L. A.; Minnaard, A. J.; Feringa, B. L. Angew. Chem., Int. Ed.
2001, 40, 927-930. (c) Arnold, L. A.; Naasz, R.; Minnaard, A. J.; Feringa,
B. L. J. Org. Chem. 2002, 67, 7244-7254. (d) Duursma, A.; Minnaard, A.
J.; Feringa, B. L. J. Am. Chem. Soc. 2003, 125, 3700-3701.
(10) (a) van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; van Esch,
J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc.
2000, 122, 11539-11540. (b) Pen˜a, D.; Minnaard, A. J.; de Vries, J. G.;
Feringa, B. L. J. Am. Chem. Soc. 2002, 124, 14552-14553. (c) van den
Berg, M.; Minnaard, A. J.; Haak, R. M.; Leeman, M.; Schudde, E. P.;
Meetsma, A.; Feringa, B. L.; de Vries, A. H. M.; Maljaars, C. E. P.; Willans,
C. E.; Hyett, D.; Boogers, J. A. F.; Henderickx, H. J. W.; de Vries, J. G.
AdV. Synth. Catal. 2003, 345, 308-323.
substituted enones have not been used before as substrates
in the asymmetric conjugate addition of arylboronic acids
and offer the attractive feature that they lead to a benzhy-
drylic stereogenic center.14 As in the case of nitrostyrenes,
this is a frequent motif in natural products and pharmaceu-
ticals.15
(12) It should be noted that the use of equal amounts of Lx and Ly does
not necessarily have to result in a statistical mixture of the homo- and hetero-
complex.
(11) (a) Reetz, M. T.; Sell, T.; Meiswinkel, A.; Mehler, G. Angew. Chem.,
Int. Ed. 2003, 42, 790-792. (b) Pen˜a, D.; Minnaard, A. J.; Boogers, J. A.
F.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. Org. Biomol. Chem.
2003, 1, 1087-1089.
(13) The use of the small achiral ligand triphenyl phosphite in homo-
and hetero-combinations gives almost complete conversions to racemic
products, but the fact that this ligand is stable under these reaction conditions
is remarkable.
3112
Org. Lett., Vol. 5, No. 17, 2003

Also with benzylidene acetone, using hetero-combinations
of ligands has a beneficial effect on the enantioselectivity,
although the conversion does not improve as much as in the
previous case. Again a mismatched effect is found by using
the L1/ent-L2 combination (25% conversion, 0% ee).
Cyclic enones such as cyclohexenone (5) have been
extensively studied as substrates in the rhodium-catalyzed
asymmetric conjugate addition of arylboronic acids and
their derivatives and can be seen as benchmark substrates
(Scheme 3).1
minor signals for the doublets of the homo-complexes, and
two new doublets from the hetero-complex appear as the
major signals. By integration, the ratios between homo- and
hetero-complexes are readily determined (Table 1).17
Table 1. Ratios of Homo- and Hetero-Complexes
Lx/Lx
Rh(Lx)2
Rh(Lx)(Ly)
Rh(Ly)2
L1/L2
L1/L3
L2/L3
17
5
27
78
91
54
5
4
19
Scheme 3. Conjugate Addition to Cyclohexenone
It should be emphasized that for the two combina-
tions where a small and a bulky phosphoramidite are used,
L1/L2 and L1/L3, the hetero-complex is clearly the most
abundant one, while the mixture of the two bulky ligands
L2/L3 gives the expected statistical distribution.18
From these results, it can be concluded that for the first
time, more effective catalysts for asymmetric C-C bond
formation are obtained by combining chiral monodentate
ligands, compared to catalysts based on single chiral ligands.
The data for the three substrates and the 31P NMR spectra
of the rhodium-phosphoramidite complexes obtained using
ligand combinations suggest that the homo-combinations of
bulky phosphoramidites are less active and selective because
the steric hindrance prevents them from functioning properly.
In contrast, an equimolar mixture, employing a small chiral
phosphoramidite, leads to hetero-complexes with less steric
hindrance that are more active and selective catalysts. Work
to optimize the catalysts and the application to other reactions
is currently in progress.
For this substrate, the trend of decreased conversion with
increasing steric bulk is also present, although even the
catalyst based on the homo-combination of the small ligand
L1 leads to a low conversion of 26%. Here the advantage
of using hetero-combinations of monodentate ligands is
considerably more pronounced. In the case of the L1/L2
combination, the conversion almost quadruples to 93% due
to a higher catalyst activity and the ee more than doubles to
75% (this also holds for the L1/L3 and L2/L3 combination).
Additional evidence for the formation of hetero-com-
plexes of chiral monodentate phosphoramidite ligands with
Rh(acac)(C2H4)2 is obtained from their 31P NMR spectra. In
the case of the homo-combination of ligands L1-L3, one
doublet is observed showing the formation of a single Rh
complex with two monodentate phosphoramidite ligands.16
The spectra of the three hetero-combinations show only
Acknowledgment. This project was funded by the
National Research School Combination Catalysis (NRSCC)
and the European Combicat Network.
Supporting Information Available: Selected experi-
mental procedures and NMR data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL035106O
(15) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
7894-7895.
(16) Doublet due to Rh-P coupling.
(14) For a racemic example, see: Itooka, R.; Iguchi, Y.; Miyaura, N.
Chem. Lett. 2001, 722-723.
(17) See Supporting Information for details.
(18) Imbalance in homo-complex ratios is due to errors in weighing.
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