Linking structural dynamics and functional diversity in asymmetric catalysis

Article abstract of DOI:10.1021/ja900084k

Proteins, the functional molecules in biological systems, are sophisticated chemical devices thathave evolved over billions of years. Their function is intimately related to their three-dimensional structure and elegantly regulated by conformational chang

Full text of DOI:10.1021/ja900084k

Published on Web 02/20/2009
Linking Structural Dynamics and Functional Diversity in
Asymmetric Catalysis
Akihiro Nojiri, Naoya Kumagai,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo 113-0033, Japan
Received January 6, 2009; E-mail: mshibasaki@mol.f.u-tokyo.ac.jp; nkumagai@mol.f.u-tokyo.ac.jp
Abstract: Proteins, the functional molecules in biological systems, are sophisticated chemical devices that
have evolved over billions of years. Their function is intimately related to their three-dimensional structure
and elegantly regulated by conformational changes through allosteric regulators and a number of reversible
or unidirectional post-translational modifications. This functional diversification in response to external stimuli
allows for an orderly and timely progression of intra- and extracellular events. In contrast, enantioselective
catalysts generally exhibit limited conformational flexibility and thereby exert a single specific function.
Exploiting the features of conformationally flexible asymmetric ligands and the variable coordination patterns
of rare earth metals, we demonstrate dynamic structural and functional changes of a catalyst in asymmetric
catalysis, leading to two distinct reaction outcomes in a single flask.
Introduction
degree of conformational freedom remains to allow modification
of its three-dimensional shape in response to specific signals
Enantioselective catalysis has established its unwavering
position in producing enantioenriched molecules with maximum
efficiency.1 In general, conformationally rigid ligands are
preferred for metal-based catalysts because they provide a robust
asymmetric architecture for the transition state of a specific
reaction of interest.2 Rigid and multidentate ligands are favorable
to afford metal complexes with high association constants,
thereby providing stable catalysts to prevent catalyst deactiva-
tion/decomposition during the reaction. Some recent progress
has been made in using conformationally flexible organocatalysts
for enantioselective transformations.1c Enantioselective catalysts
are generally designed to exert a single function under one set
of conditions in one reaction flask. The same catalyst can
sometimes give rise to different products under an alternative
set of conditions;3 however, it is rare for a single metal-based
or organocatalyst to be able to promote multiple highly
enantioselective transformations within the same flask in
response to an external signal.4-7
such as the noncovalent binding of allosteric regulators, or
covalent modification of structure-determining functionalities
(e.g., acetylation/phosphorylation of H-bond donors and ioniz-
able groups, cleavage of peptide domains). A particularly
intriguing feature of functional proteins and enzymes is the
(3) Selected examples of enantioselectivity reversal by different metals:
(a) Nishibayashi, Y.; Segawa, K.; Ohe, K.; Uemura, S. Organome-
tallics 1995, 14, 5486. (b) Evans, D. A.; MacMillan, D. W. C.;
Campos, K. R. J. Am. Chem. Soc. 1997, 119, 10859. (c) Murakami,
M.; Itami, K.; Ito, Y. J. Am. Chem. Soc. 1999, 121, 4130. (d) Yabu,
K.; Masumoto, S.; Yamasaki, S.; Hamashima, Y.; Kanai, M.; Du, W.;
Curran, D. P.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 9908. (e)
Bertozzi, F.; Pineschi, M.; Macchia, F.; Arnold, L. A.; Minnaard, A. J.;
Feringa, B. L. Org. Lett. 2002, 4, 2703. (f) Du, D. M.; Lu, S. F.;
Fang, T.; Xu, J. J. Org. Chem. 2005, 70, 3712. By additives: (g)
Kobayashi, S.; Ishitani, H. J. Am. Chem. Soc. 1994, 116, 4083. (h)
Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. (i) Kawamura, M.;
Kobayashi, S. Tetrahedron Lett. 1999, 40, 3213. (j) Trost, B. M.;
Fettes, A.; Shireman, B. T. J. Am. Chem. Soc. 2004, 126, 2660. (k)
Lutz, F.; Igarashi, T.; Kawasaki, T.; Soai, K. J. Am. Chem. Soc. 2005,
127, 12206. (l) Mao, J.; Zhang, Z.; Wang, R.; Wu, F.; Lu, S. J. Mol.
Catal., A 2005, 225, 33. By temperature: (m) Sibi, M. P.; Gorikunti,
U.; Liu, M. Tetrahedron 2002, 58, 8357. (n) Casey, C. P.; Martins,
S. C.; Fagan, M. A. J. Am. Chem. Soc. 2004, 126, 5585. By solvent: (o)
Kanai, M.; Koga, K.; Tomioka, K. J. Chem. Soc., Chem. Commun.
1993, 1248. (p) Johannsen, M.; Jørgensen, K. A. Tetrahedron 1996,
52, 7321. (q) Zhou, J.; Ye, M. C.; Huang, Z. Z.; Tang, Y. J. Org.
Chem. 1998, 63, 5483. (r) Arsenyadis, S.; Valleix, A.; Wagner, A.;
Mioskowski, C. Angew. Chem., Int. Ed. 2004, 43, 3314Others: (s)
Nomura, N.; Mermet-Bouvier, Y. C.; RajanBabu, T. V. Synlett 1996,
745. (t) Evans, D. A.; Kozlowski, M. C.; Murray, J. A.; Burgey, C. S.;
Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999,
121, 669. (u) Clyne, D. S.; Mermet-Bouvier, Y. C.; Nomura, N.;
RajanBabu, T. V. J. Org. Chem. 1999, 64, 7601. (v) Kuwano, R.;
Sawamura, M.; Ito, Y. Bull. Chem. Soc. Jpn. 2000, 73, 2571. (w)
Kitagawa, O.; Matsuo, S.; Yotsumoto, K.; Taguchi, T. J. Org. Chem.
2006, 71, 2524. (x) Shao, Z.; Wang, J.; Ding, K.; Chan, A. S. C. AdV.
Synth. Catal. 2007, 349, 2375.
Proteins, on the other hand, are capable of carrying out
multiple functions (including highly enantioselective transfor-
mations) in response to external signals (Figure 1a). Their
polypeptide-based structure displays a distinct three-dimensional
architecture through noncovalent interactions, while a reasonable
(1) (a) Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds. ComprehensiVe
Asymmetric Catalysis; Springer: Berlin, 1999 and 2003 (Suppl. 1);
Vols. I-III. (b) Ojima, I., Ed. Catalytic Asymmetric Synthesis; Wiley:
New York, 2000. (c) Barkessel, A., Gro¨ger, H., Eds. Asymmetric
Organocatalysis; Wiley: Weinheim, 2006. (d) Mitchinson, A.; Finkel-
stein, J. Nature 2008, 455, 303. and the following articles on small-
molecule catalysis.
(2) In contrast, various kinds of conformationally flexible organocatalysts
have been developed, see ref 1c and references cited therein. For an
example on the importance of catalyst flexibility in metal-based
enantioselective catalysis, see: Malcolmson, S. J.; Meek, S. J.;
Elizabeth, S. S.; Schrock, R. R.; Hoveyda, A. H. Nature 2008, 456,
933.
(4) Anexampleofasymmetriccatalystswithinduced-fitmechanism:Kawabata,
T.; Nagato, M.; Takasu, K.; Fuji, K. J. Am. Chem. Soc. 1997, 119,
3169.
9
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2009 American Chemical Society
J. AM. CHEM. SOC. 2009, 131, 3779–3784 3779

A R T I C L E S
Nojiri et al.
Scheme 1. anti- and syn-Selective Catalytic Asymmetric Mannich-
Type Reaction of R-Cyanocyclopentanone 2a and N-Boc Imine 3a
with the 1/RE Catalyst
Figure 1. Structural dynamics and functional diversity in (a) a biomac-
romolecule and (b) an enantioselective catalyst.
coordination patterns to REs would allow the formation of
alternative structures capable of exerting different catalytic
functions. By exploiting these chemical properties, we envi-
sioned the development of a catalytic system that allowed for
timely functional modifications.
seamless linking of structural dynamics and their functional
diversity, namely that their structural change leads to turning
on/off their function or acquiring another function, enabling the
regulation of timely intra- and extracellular events to progress
with elegant synergy.8 The logic of functional molecules that
exploit structural dynamics in biological systems inspired us to
explore the timely functional change of an enantioselective
catalyst in which the functional switching property is encoded
by its structural dynamics. Molecular dynamics is currently of
intense interest in the field of molecular machines,9 but its
significance does not receive much attention in enantioselective
catalysis. Herein, we report our attempt to link structural
dynamics and functional switching in an artificial catalyst,
through which we demonstrate diastereoselectivity switching
in a single flask.
We hypothesized that a catalyst comprising small amide-based
ligands derived from R-amino acids and rare earth metals (REs)
would constitute a catalytic system well suited for our purpose
to achieve protein-like multifunctionality through flexible
structural dynamics,10 because (1) amide-based ligands possess
reasonable rigidity (planar amide) and conformational flexibility
(R-carbon), and (2) REs have multiple coordination modes and
coordination numbers, depending on the peripheral chemical
environments (Figure 1b).11 In this combination, the possibility
of multiple ligand coordination modes together with variable
Results and Discussion
Asymmetric Mannich-Type Reaction with 1/RE Catalyst.
Previously, we reported that a 1/Sc catalyst, prepared by mixing
amide-based ligand 112 and Sc(OiPr)3 in a ratio of 2:1, allowed
for a catalytic asymmetric anti-selective Mannich-type reaction
of 2-cyanocyclopentanone (2a) and N-Boc imine 3a to afford
anti-4aa with high enantiomeric excess (Scheme 1a).13,14 The
protocol enabled the construction of a chiral quaternary carbon
via intermolecular asymmetric catalysis, which remains a
formidable task in modern organic synthesis,15 and was
(10) Recent selected examples of asymmetric catalysis by conformationally
dynamic peptide-based catalysts: (a) Miller, S. J.; Copeland, G. T.;
Papaioannou, N.; Horstmann, T. E.; Ruel, E. M. J. Am. Chem. Soc.
1998, 120, 1629. (b) Fierman, M. B.; O’Leary, D. J.; Steinmetz, W. E.;
Miller, S. J. J. Am. Chem. Soc. 2004, 126, 6967. (c) Zhao, Y.; Rodrigo,
J.; Hoveyda, A. H.; Snapper, M. C. Nature 2006, 443, 67. For recent
reviews on small peptide-based asymmetric catalysis, see: (d) Hoveyda,
A. H.; Hird, A. W.; Kacprzynski, M. A. Chem. Commun. 2004, 1779.
(e) Blank, J. T.; Miller, S. J. Biopolymers 2006, 84, 38. (f) Colby
Davie, E. A.; Mennen, S. M.; Xu, Y.; Miller, S. J. Chem. ReV. 2007,
107, 5759.
(11) (a) Cotton, S., Ed. Lanthanide and Actinide Chemistry; Wiley: New
York, 2006. For reviews, see: (b) Aspinall, H. C. Chem. ReV. 2002,
102, 1807. (c) Tsukube, H.; Shinoda, S. Chem. ReV. 2002, 102, 2389.
(d) Parker, D. Chem. Soc. ReV. 2004, 33, 156. (e) Bari, L. D.;
Salvadori, P. Coord. Chem. ReV. 2005, 249, 2854, and references cited
therein.
(5) A review on asymmetric activation and deactivation, see: Mikami,
K.; Aikawa, K. New Frontiers in Asymmetric Catalysis; Mikami, K.,
Lautens, M., Eds.; Wiley: New York, 2007; pp 221-257.
(6) An example of an artificial allosteric catalyst, see: (a) Gianneschi,
N. C.; Bertin, P. A.; Nguyen, S. T.; Mirkin, C. A.; Zakharov, L. N.;
Rheingold, A. L. J. Am. Chem. Soc. 2003, 125, 10508 An example of
photoswichable achiral catalyst achieving ON-state and OFF-state, see:
(b) Peters, M. V.; Stoll, R. S.; Ku¨hn, A.; Hecht, S. Angew. Chem.,
Int. Ed. 2008, 47, 5968. (c) Stoll, R. S.; Peters, M. V.; Kuhn, A.;
Heiles, S.; Goddard, R.; Bu¨hl, M.; Thiele, C. M.; Hecht, S. J. Am.
Chem. Soc. 2009, 131, 357.
(12) Ligand 1 was prepared from L-valine in a four-step chromatography
free procedure. For the utility of 1, see: (a) Mashiko, T.; Hara, K.;
Tanaka, D.; Fujiwara, Y.; Kumagai, N.; Shibasaki, M. J. Am. Chem.
Soc. 2007, 129, 11342. (b) Nitabaru, T.; Kumagai, N.; Shibasaki, M.
Tetrahedron Lett. 2008, 49, 272. (c) Mashiko, T.; Kumagai, N.;
Shibasaki, M. Org. Lett. 2008, 10, 2725.
(13) Nojiri, A.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130,
5630 In this paper, CH2Cl2 was used as solvent. The diastereo- and
enantioselectivity in different solvents are as follows: CH2Cl2: syn/
anti ) 9/91, 94% ee, toluene: syn/anti ) 12/88, 85% ee, THF: syn/
anti ) 8/92, 80% ee, ether: syn/anti ) 8/92, 90% ee, CH3CN:
syn/anti ) 8/92, 91% ee, acetone: syn/anti ) 8/92, 91% ee.
(14) For reviews on R-cyanocarboanions, see: (a) Arseniyadis, S.; Kyler,
K. S.; Watt, D. S. Org. React. 1984, 31, 1. (b) Fleming, F. F.; Shook,
B. C. Tetrahedron 2002, 58, 1. (c) Fleming, F. F.; Iyer, P. S. Synthesis
2006, 893.
(7) Selected examples of enantioselective catalysts comprising confor-
mationally dynamic peptide-based ligand and metal cation, see: (a)
Hird, A. W.; Hoveyda, A. H. J. Am. Chem. Soc. 2007, 127, 14988.
(b) Wieland, L. C.; Deng, H.; Snapper, M. C.; Hoveyda, A. H. J. Am.
Chem. Soc. 2007, 127, 15453. (c) Fu, P.; Snapper, M. C.; Hoveyda,
A. H. J. Am. Chem. Soc. 2008, 130, 5530.
(8) (a) Ptashne, M.; Gann, A. Curr. Biol. 1998, 8, R812. (b) Harrison,
S. C. Nat. Struct. Mol. Biol. 2004, 11, 12. (c) Heilmann, I.; Pidkowich,
M. S.; Girke, T.; Shanklin, J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
10266.
(15) For recent reviews: (a) Corey, E. J.; Guzman-Perez, A. Angew. Chem.,
Int. Ed. 1998, 37, 388. (b) Christoffers, J.; Mann, A. Angew. Chem.,
Int. Ed. 2001, 40, 4591. (c) Douglas, C. J.; Overman, L. E. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5363. (d) Trost, B. M.; Jiang, C.
Synthesis 2006, 369.
(9) Balzani, V.; Credi, A.; Venturi, M., Eds. Molecular DeVices and
Machines, 2nd ed.; Wiley: Weinheim, 2008.
9
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Structure/Function Flexibility in Asymmetric Catalysts
A R T I C L E S
Table 1. syn-Selective Catalytic Asymmetric Mannich-Type Reaction with the 1/Er Catalyst
cyanoketone 2
imine 3
entry
x
n
Ar
product
yielda (%)
anti/syn
ee (syn) (%)
1
2
1
5
5
2
2
2
2
2
2
2
2
2
2
1
1
2
3
1
1
1
1
1
1
1
1
1
1
2a
Ph
Ph
Ph
Ph
3a
3a
3a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
4aa
4aa
4ba
4ca
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
4aj
4ak
92
99
97
79
99
86
96
99
95
91
99
82
99
99
6/94
15/85
13/87
30/70
5/95
5/95
7/93
4/96
5/95
7/93
4/96
4/96
7/93
4/96
95
98
97
94
99
97
92
99
91
99
99
92
84
96
2b
3c
4c
5
2a
2b
2c
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2-MeC6H4
4-MeC6H4
2-naphthyl
2-ClC6H4
4-ClC6H4
2-FC6H4
2-MeOC6H4
4-MeOC6H4
2-furyl
6
7d
8
9
10
11
12
13
14
3-thienyl
a Isolated yield. b Reaction time was 3 h. c Reaction time was 20 h. d Dichloromethane was used as solvent.
Figure 4. CD spectra of the 1/Sc/Er solution in ethyl acetate with a variable
1/Sc/Er ratio. (a) 1/Sc ) 2:1; (b) 1/Sc/Er ) 4:1:1; (c) 1/Sc/Er ) 3:1:1; (d)
1/Sc/Er ) 4:2:1.
Figure 2. CD spectra of (a) ligand 1, (b) the 1/Sc ) 2:1 catalyst, and (c)
the 1/Er ) 2:1 catalyst in ethyl acetate.
Scheme 2. Catalytic Asymmetric Mannich-Type Reaction of 2a and
3a Using 1/Sc/Er ) 4:1:1 Solution as a Catalyst
mode of the two phenol moieties of 1. The high stereoselectivity
would be rationalized by assuming a well-organized association
at the transition state from a nonordered reaction mixture
ensemble. The nondefined structure of the 1/Sc catalyst might
indicate that the catalytic system of the 1/RE retains the potential
to provide a catalyst with a different structural motif in different
reaction ensembles. This assumption prompted us to explore
the possibility of structural/functional modifications of the
catalyst using this reaction system. In our search for other 1/RE
catalysts, we found that a 1/Er catalyst, prepared from 1 and
Er(OiPr)3 in a ratio of 2:1, displayed remarkable diastereose-
lectivity reversal compared to the 1/Sc catalyst to give syn-4aa
with 99% ee under otherwise identical reaction conditions
Figure 3. Initial rate kinetics of the reaction of 2a and 3a with four different
catalysts, 1/Er, 1/Sc, Er(OiPr)3, and Sc(OiPr)3. The catalyst loading was 5
mol % each (based on RE). The reactions were conducted at -30 °C for
accurate measurement. kEr and kSc were the observed rate constants for the
1/Er catalyst and 1/Sc catalyst, respectively.
complementary to other syn-selective Mannich-type reactions.16,17
Particularly noteworthy is that the 1/Sc catalyst did not form a
distinct structure on the basis of 1H NMR analysis, likely
because several complexation patterns would be possible due
to the structural flexibility and the monodentate coordination
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J. AM. CHEM. SOC. VOL. 131, NO. 10, 2009 3781

A R T I C L E S
Nojiri et al.
Scheme 3. Catalytic Asymmetric Mannich-Type Reaction of 2a and
3a Using a Catalyst Prepared by Mixing a Premixed (R)-1/Sc
Solution and a (S)-1/Er Solution
shown in Figure 2. Clear differences in the spectral pattern were
observed between the CD spectra of 1, and the 1/Sc ) 2:1 and
1/Er ) 2:1 solution, suggesting that a chiroptically different
1/RE assembly developed in each solution (Figure 2). Due to
the exquisite combination of factors; (1) structural flexibility
of the chiral ligand 1; (2) high coordination number of RE; and
(3) availability of various coordination patterns of RE, 1
provided chiroptically different asymmetric catalysts in response
to the properties of the RE, consequently affording anti and
syn products with high enantioselectivity under otherwise
identical reaction conditions. An initial rate kinetics study
revealed clear ligand acceleration in both Sc and Er cases (Figure
3).20 Also worth noting is that 1/Er exhibited higher catalytic
activity than the Sc counterparts. This can be attributed to the
different three-dimensional architectures of these catalysts.21 A
significant deviation from linearity between the enantiopurity
of 1 and that of the product in both the Sc and Er cases suggested
the involvement of multiple molecules of 1 around the metal
center at the transition state.22
(Scheme 1b).3,18,19 Determination of the absolute configuration
of syn-4aa by X-ray crystallography revealed that enantiose-
lection of the enolate derived from 2a was inverted. The reversal
of diastereoselectivity was uniformly observed with a broad
range of substrates (Table 1). Particularly noteworthy is that
enhanced catalytic activity was observed with the 1/Er catalyst,
allowing the reaction to reach completion after 1 h of stirring
at 0 °C with 2 mol % of catalyst loading. A comparable level
of stereoselectivity was attained with as little as 1 mol % of
catalyst loading with an extended reaction time (entry 2).
Detrimental effects on the reaction time were detected in the
reaction with 6- and 7-membered R-cyanoketones 2b and 2c,
and lower diastereoselectivity was observed (entries 3,4).
Generally, a high syn-selectivity (anti/syn ) 7/93-4/96) and
enantioselectivity (91-99% ee) were observed in the reaction
with a wide range of aromatic N-Boc imines 3, including those
with heteroaromatic functionality (entries 5-12, 14). Lower
enantioselectivity was observed with imine with a 2-furyl
substituent (entry 13).
The Catalyst in the Presence of Both Sc and Er. With a
suitable catalytic system of 1/RE in hand, in which 1 displayed
different assembly patterns in response to different REs, we
envisioned in situ structural/functional modifications in the
course of the catalytic asymmetric Mannich-type reaction. An
attempted reaction of 2a and 3a with the 1/Sc/Er ) 4:1:1 catalyst
afforded the anti-product 4aa preferentially (anti/syn ) 89/11)
in 88% ee (Scheme 2), comparable to that obtained with the
1/Sc catalyst (Scheme 1a). If both 1/Sc (1/Sc ) 2:1) and 1/Er
(1/Er ) 2:1) catalysts were formed in a comparable quantity
and promoted the reaction independently, the consequence
should have been a syn-selective reaction because the initial
rate kinetics experiment revealed that the reaction rate with the
1/Er (rate constant kEr ) 1.64 × 10-5 mol L-1 s-1) catalyst was
7.6-fold faster than that of the 1/Sc catalyst (kSc ) 2.16 × 10-6
mol L-1 s-1) (Figure 3). At this point, there were two
possibilities: (1) a 1/Sc/Er heteropolymetallic complex was
formed and promoted the anti-selective reaction with enanti-
oselectivity similar to that obtained with 1/Sc; or (2) a 1/Sc
catalyst was preferentially formed over the 1/Er catalyst,
affording a similar reaction output to that of the 1/Sc catalyst.
The CD spectra of the 1/Sc/Er ) 4:1:1, 3:1:1, and 4:2:1 solutions
would represent the formation of the aggregate, which had
chiroptical properties similar to those of the original anti-
selective catalyst 1/Sc ) 2:1 (Figure 4). In particular, the CD
spectral pattern of 1/Sc/Er ) 4:2:1 showed a nearly perfect
match with that of 1/Sc ) 2:1, suggesting that most Er3+ would
be excluded from the coordination site of 1 due to a competitive
coordination of Sc3+ to 1. The formation of the 1/Sc/Er
heteropolymetallic aggregate showing a similar CD pattern
would be less likely. The lability of 1 in the present catalytic
system was examined in the following attempted reaction. When
separate solutions of preformed (R)-1/Sc ) 2:1 and (S)-1/Er )
2:1 solution were mixed together and the resulting solution was
CD and Kinetic Analyses of the 1/Sc and 1/Er Catalyst. Of
prime importance in the present catalytic system is the origin
of diastereoswitching. The paramagnetic nature of Er hampered
a detailed NMR analysis of the 1/Er catalyst. Circular dichroism
(CD) spectra of 1/Sc and 1/Er catalyst provided insight into
the differences in the assembly states of each catalytic system.
The CD spectrum of 1 at the UV-vis region in ethyl acetate is
(16) For recent reviews on direct Mannich reactions using unmodified
pronucleophiles, see: (a) Shibasaki, M.; Matsunaga, S. J. Organomet.
Chem. 2006, 691, 2089. (b) Ting, A.; Schaus, S. E. Eur. J. Org. Chem.
2007, 5797. For general reviews on catalytic asymmetric Mannich
reactions: (c) Kobayashi, S.; Ueno, M. In ComprehensiVe Asymmetric
Catalysis,Supplement 1; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds; Springer: Berlin, 2003; Chapter 29.5, p 143. (d) Friestad, G.;
Mathies, A. K. Tetrahderon 2007, 63, 2541.
(17) For selected examples of catalytic asymmetric Mannich reactions with
1,3-dicarbonyl compounds generating quaternary carbon stereocenters,
see: (a) Marigo, M.; Kjærsgaard, A.; Juhl, K.; Gathergood, N.;
Jørgensen, K. A. Chem. Eur. J. 2003, 9, 2359. (b) Hamashima, Y.;
Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi, N.; Sodeoka, M.
Angew. Chem., Int. Ed. 2005, 44, 1525. (c) Ting, A.; Lou, S.; Schaus,
S. E. Org. Lett. 2006, 8, 2003. (d) Tillman, A. L.; Ye, J.; Dixon, D. J.
Chem. Commun. 2006, 1191. (e) Yamaoka, Y.; Miyabe, H.; Yoshi-
zumi, Y.; Takemoto, Y. Synthesis 2007, 2571. (f) Chen, Z.; Morimoto,
H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 2170.
For selected examples of catalytic asymmetric Mannich reactions with
1,3-dicarbonyl compounds generating tertiary stereocenters, see: (g)
Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356. (h)
Lou, S.; Taoka, B. M.; Ting, A.; Schaus, S. E. J. Am. Chem. Soc.
2005, 127, 11256. (i) Song, J.; Wang, Y.; Deng, L. J. Am. Chem.
Soc. 2006, 128, 6048. (j) Sasamoto, N.; Dubs, C.; Hamashima, Y.;
Sodeoka, M. J. Am. Chem. Soc. 2006, 128, 14010.
(20) The rate acceleration suggested the involvement of hydrogen-bonding
to promote the reaction and enhance the stereodiscrimination at the
transition state. The hydrogen-bonding in peptide-based catalysts is
well-documented, see: (a) Copeland, G. T.; Miller, S. J. J. Am. Chem.
Soc. 2001, 123, 6496. (b) Sculimbrene, B. R.; Morgan, A. J.; Miller,
S. J. J. Am. Chem. Soc. 2002, 124, 11653. (c) Jakobsche, C. E.; Peris,
G.; Miller, S. J. Angew. Chem., Int. Ed. 2008, 47, 6707, and references
therein.
(18) A general review on enantioselectivity reversal using a single chiral
source, see: Tanaka, T.; Hayashi, M. Synthesis 2008, 3361, and
references therein.
(19) A notable example of an asymmetric catalyst exhibiting sharp enantio-
switching, depending on the assembly state of the catalyst, see: Kato,
N.; Mita, T.; Kanai, M.; Therrien, B.; Kawano, M.; Yamaguchi, K.;
Danjo, H.; Sei, Y.; Sato, A.; Furusho, S.; Shibasaki, M. J. Am. Chem.
Soc. 2006, 128, 6768.
(21) We cannot exclude the possibility that a higher ligand exchange rate
of Er would contribute to enhanced catalyst turnover.
(22) See Supporting Information for details.
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Structure/Function Flexibility in Asymmetric Catalysts
A R T I C L E S
Figure 5. CD spectra of the 1/Sc and 1/Er catalyst solution with variable 1/RE ratio.
Scheme 4. Dynamic Structural and Functional Change of the 1/RE Catalyst
used as catalyst (1/Sc/Er ) 4:1:1), nearly racemic anti-4aa was
obtained, indicating that the association between 1-Sc and 1-Er
was not kinetically stable and 1 was involved in a dynamic
exchange with Sc3+ and Er3+ (Scheme 3). The CD spectra of
the 1/Sc solution with variable ratios showed monotonic
transitions as the amount of Sc3+ increased (Figure 5A). On
the other hand, that of 1/Er showed an apparent biphasic
transition and negligible change at a low Er concentration
(Figure 5B), suggesting that the association of 1/Er was weaker
than that of 1/Sc. These results suggest that 1/Sc aggregation is
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J. AM. CHEM. SOC. VOL. 131, NO. 10, 2009 3783

A R T I C L E S
Nojiri et al.
preferentially formed in 1/Sc/Er ) 4:1:1 to exhibit a reaction
outcome similar to that of the 1/Sc ) 2:1 catalyst, enabling a
unidirectional catalyst modification.
artificial asymmetric catalyst through dynamic structural
modifications.
Conclusion
Timely Structural Change and Functional Modification of
the 1/RE catalyst. We next explored the possibility that a
dynamic functional change of the enantioselective catalyst
occurred in the course of the reaction. We designed the reaction
system as follows; (1) a Mannich-type reaction of 2a (2.4 equiv)
and 3e (1.0 equiv) was conducted with the 1/Er ) 4:1 catalyst
(1: 10 mol %, Er(OiPr)3 2.5 mol %) to form syn-4ae; (2) then
Sc(OiPr)3 (2.5 mol %) was added to modify the catalyst
structure, and another imine 3a (1.0 equiv) was introduced to
afford anti-4aa. The catalyst switched gears and engaged in an
anti-selective reaction to afford anti-4aa with high diastereo-
and enantioselectivity (Scheme 4a). In this process, the structure
of the catalyst was changed in response to the property of the
RE, affording both syn and anti products in a single flask.23
Structural changes of the catalyst upon the addition of Sc(OiPr)3
were traced by CD analysis of the reaction mixture as illustrated
((i) before the addition of Sc(OiPr)3, (ii) after the addition of
Sc(OiPr)3). Other combinations of substrates, 2a and 3b for a
syn-selective reaction and 2a and 3a for an anti-selective
reaction, were also examined, and similar levels of functional
switches of the catalyst were observed (Scheme 4b). The process
was also operative in the reaction of two different R-cyanoke-
tones, i.e., the first syn-selective reaction of 2a (1.0 equiv) and
3a (2.4 equiv) with the 1/Er ) 4:1 catalyst, and the following
addition of 2c (1.0 equiv) after the structural change with
Sc(OiPr)3 afforded syn-4aa and anti-4ca (Scheme 4c). These
results are indicative of a timely functional change of the
We revealed that the ligand 1 provides enantioselective
catalysts with different chiroptical properties upon complexation
with Sc(OiPr)3 or Er(OiPr)3, allowing for either an anti- or syn-
selective catalytic asymmetric Mannich-type reaction of R-cy-
anoketones 2 and N-Boc imines 3. The structural dynamics and
functional diversity of the present catalytic system culminated
in timely functional switching over the course of the reaction.
Although three-dimensional conformational change in response
to external stimuli is intimately linked to functional diversity
in biomacromolecular systems and ubiquitously utilized as a
means of regulation, such a process has been underutilized in
the field of asymmetric catalysis. The present catalytic system
is an important contribution to chemistry in which multifunc-
tionality is encoded in the intrinsic structural dynamics of the
catalyst, ultimately leading to the construction of an artificial
system in which dozens of multifunctional catalysts endowed
with timely regulable processes work in a synergistic manner
like a cellular system prototype. The development of enanti-
oselective catalysts that enable reversible functional switching
will be the focus of future investigations.
Acknowledgment. This work was financially supported by
Grant-in-Aid for Scientific Research (S) and Grant-in-Aid for Young
Scientist (B) from JSPS. Prof. T. Ohwada, Dr. S. Uchiyama, and
Mr. T. Hori at the University of Tokyo, and Dr. M. Shiro at Rigaku
Corporation are gratefully acknowledged for technical assistance.
We thank Dr. N. Shepherd for fruitful discussion.
Supporting Information Available: Experimental details and
characterization of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(23) The reaction with the opposite order of metal source addition did not
show functional changes as expected from the results of the previous
section. Details are shown in Supporting Information.
JA900084K
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3784 J. AM. CHEM. SOC. VOL. 131, NO. 10, 2009