A R T I C L E S
Gridnev et al.
Scheme 1. Reactions of Chiral Amido Complexes with
Pronucleophiles
The mechanistic aspects of enantioselective reduction with
bifunctional catalysts are intensively studied experimentally and
computationally.2,4 It is commonly accepted that hydrogen
transfer between ketones and alcohols occurs through a six-
membered pericyclic transition state, in which the substrate can
be activated in a concerted manner as shown in Figure 1.
ing organic moiety instead of the hydrogen atom. This similarity
initially led to the conclusion that the reaction with a second
player in the C-C bond formation reaction might proceed via
an analogous transition structure, i.e. direct transfer of the metal
bonded nucleophilic part to the acceptor assisted by coordination
of the latter to the NH2 group of the amino complex. In fact,
we found that the chiral Ru catalysts, Ru(N-sulfonylated
dpen)(η6-arene) 1, efficiently effected enantioselective Michael
addition of 1,3-dicarbonyls to cyclic enones or nitroalkenes to
give the corresponding chiral adducts with excellent ee’s.11
There also are distinctions between the structures of amino
complexes having a hydrogen atom or an organic moiety bonded
to the metal. In the former case, the electronic density acquired
by the proton upon the formation of the M-H bond is localized
on the hydride ligand. Whereas when a conjugated organic
moiety binds to the metal, the charge can be effectively
delocalized, and the reactive center can be shifted to another
part of the molecule. Also, replacing the hydrogen atom with
any organic moiety dramatically increases the spatial hindrance
nearby the metal atom which can evidently prevent the formation
of a transition state similar to the hydrogen transfer case.
In this paper we report an experimental mechanistic study
on these types of C-C bond formation reactions with bifunc-
tional catalysts, combined with a computational investigation
of the catalytic cycle and the origin of enantioselectivity. Scheme
2 illustrates a schematic catalytic cycle for the enantioselective
Figure 1. A possible transition state for the hydrogen transfer between
ketones and alcohols.
There are several important implications of this mechanism.
First, it demonstrates that the double bond of the prochiral
carbonyl compound is fixed by two binding sites of the catalyst
in a dual activation mode, thus opening the door for effective
stereodiscrimination. Next, since the metal center of the
bifunctional catalyst shown in Figure 1 has a coordinatively
saturated environment, the reacting substrate does not interact
directly with the metal center, thus its activation with the catalyst
takes place in the outer sphere. This kind of transition structure
results in the complete reversibility of the reaction which is
practically important, since the same catalytic systems can be
used either for enantioselective reduction of ketones or for
kinetic resolution of alcohols via selective oxidation, as well
as for rapid racemization of chiral alcohols with an achiral
bifunctional catalyst system.4f,5
On the other hand, the enantioselctive C-C bond formation
with bifunctional molecular catalysts has been much less studied.
The known examples are Shibasaki’s chiral multimetallic
centered catalysts,6 Ito and Hayashi’s chiral gold catalysts,7a
Mezzetti’s ruthenium PNNP complexes,8 and Ru hydride
borohydride complexes of Morris.9 We have recently found that
chiral amido complexes have a sufficient Brønsted basicity to
effect deprotonation of certain acidic pronucleophiles, leading
to the correponding amino complex that binds the deprotonated
nucleophile as shown in Scheme 1.10 Hence, formally the
situation resembles the case of asymmetric transfer hydrogena-
tion (Figure 1), the metal atom being bonded to the correspond-
(6) (a) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl.
1997, 36, 1236. (b) Shibasaki, M.; Kanai, M.; Funahashi, K. Chem.
Commun. 2002, 1989. (c) Shibasaki, M.; Yoshikawa, Y. Chem. ReV.
2002, 102, 2187. (d) Oisaki, K.; Zhao, D.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2007, 129, 7439. (e) Shibasaki, M.; Matsunaga,
S.; Kumagai, N. Synlett 2008, 1583. Nitabaru, T.; Nojiri, A.;
Kobayashi, M.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009,
131, 13860. (f) Mashiko, T.; Kumagai, N.; Shibasaki, M. J. Am. Chem.
Soc. 2009, 131, 14990. (g) Shibasaki, M.; Kanai, M.; Matsunaga, S.;
Kumagai, N. Acc. Chem. Res. 2009, 42, 1117.
(7) Early review articles for enantioselective C-C bond formation with
bifunctional catalysts: (a) Sawamura, M.; Ito, Y. Chem. ReV., 1992,
92, 857. (b) Steinhagen, H.; Helmchen, G. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2339. (c) van den Beuken, E. K.; Feringa, B. L.
Tetrahedron 1998, 54, 12985. (d) Rowlands, G. J. Tetrahedron 2001,
57, 1865. (e) Gro¨ger, H. Chem.sEur. J. 2001, 7, 5246. (f) Ma, J.-A.;
Cahard, D. Angew. Chem., Int. Ed. 2004, 43, 4566.
(8) (a) Althaus, M.; Bonnacorsi, C.; Mezzetti, A.; Santorno, F. Organo-
metallics 2006, 25, 3108. (b) Santoro, F.; Althaus, M.; Bonaccorsi,
C.; Gischig, S.; Mezzetti, A. Organometallics 2008, 27, 3866. (c)
Schotes, C.; Mezzetti, A. J. Am. Chem. Soc. 2010, 132, 3652.
(9) (a) Guo, R.; Morris, R. H.; Song, D. J. Am. Chem. Soc. 2005, 127,
516. (b) Clapham, S. E.; Guo, R.; Zimmer-De Iuliis, M.; Rasool, N.;
Lough, A.; Morris, R. H. Organometallics 2006, 25, 5477.
(4) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1995, 117, 7562. (b) Takehara, J.; Hashiguchi, S.; Fujii,
A.; Inoue, S.; Ikariya, T.; Noyori, R. Chem. Commun. 1996, 233. (c)
Gao, J.-X.; Ikariya, T.; Noyori, R. Organometallics 1996, 15, 1087.
(d) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R.
J. Am. Chem. Soc. 1996, 118, 2521. (e) Uematsu, N.; Fujii, A.;
Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118,
4916. (f) Hashiguchi, S.; Fujii, A.; Haack, K.-J.; Matsumura, T.;
Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 288.
(g) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738. (h) Ikariya, T.; Hashiguchi, S.; Murata,
K.; Noyori, R. Org. Synth. 2005, 82, 10.
(10) (a) Murata, K.; Konishi, H.; Ito, M.; Ikariya, T. Organometallics 2002,
21, 253. (b) Koike, T.; Ikariya, T. AdV. Synth. Catal. 2004, 346, 37.
(c) Koike, T.; Ikariya, T. Organometallics 2005, 24, 724.
(11) (a) Watanabe, M.; Murata, K.; Ikariya, T. J. Am. Chem. Soc. 2003,
125, 7509. (b) Wang, H.; Watanabe, M.; Ikariya, T. Tetrahedron Lett.
2005, 46, 963. (c) Watanabe, M.; Ikagawa, H.; Wang, H.; Murata,
K.; Ikariya, T. J. Am. Chem. Soc. 2004, 126, 11148. (d) Ikariya, T.;
Wang, H.; Watanabe, M.; Murata, K. J. Organomet. Chem. 2004, 689,
1377.
(5) (a) Arita, S.; Koike, T.; Kayaki, Y.; Ikariya, T. Angew. Chem., Int.
Ed. 2008, 47, 2447. (b) Ito, M.; Osaku, A.; Kitahara, S.; Hirakawa,
M.; Ikariya, T. Tetrahedron Lett. 2003, 44, 7521.
9
16638 J. AM. CHEM. SOC. VOL. 132, NO. 46, 2010