Entropy-controlled catalytic asymmetric 1,4-type Friedel-crafts reaction of phenols using conformationally flexible guanidine/bisthiourea organocatalyst

Article abstract of DOI:10.1002/anie.201003172

Soft and weak cooperation: Conformationally flexible organic compounds were found to promote the title transformation. These "soft" organocatalysts, which are able to control processes through the differential activation entropies (ΔΔS*_S-R) of

Full text of DOI:10.1002/anie.201003172

Angewandte
Chemie
DOI: 10.1002/anie.201003172
Synthetic Methods
Entropy-Controlled Catalytic Asymmetric 1,4-Type Friedel–Crafts
Reaction of Phenols Using Conformationally Flexible Guanidine/
Bisthiourea Organocatalyst**
Yoshihiro Sohtome,* Bongki Shin, Natsuko Horitsugi, Rika Takagi, Keiichi Noguchi, and
Kazuo Nagasawa*
One of the most important aspects of protein function is the
motion that occurs in response to substrate binding.[1] In the
dynamics of enzyme catalysis, multiple weak hydrogen-
bonding interactions[2] in the polypeptide that are controlled
by interrelated enthalpy and entropy changes play a signifi-
cant role in governing the conformational changes that take
place.[3] In contrast, the development of asymmetric organo-
catalysts has rarely focused on hydrogen-bond donors[4–8] that
have conformationally flexible scaffolds[9–11] as a likely con-
sequence of difficulties in controlling the conformation of
acyclic skeletons.[12] However, recently our research group has
successfully demonstrated the utility of conformationally
flexible guanidine/bisthiourea organocatalysts 1 for organo-
catalytic carbon–carbon bond-forming reactions.[9] Herein, we
describe studies that have led to the development of new
acyclic C3-linked guanidine/bisthiourea organocatalysts 2.
Analysis of these processes shows that the catalytic effect
resides in a trade off between enthalpies and entropies of
activation and reveals the existence of dramatic concentration
effects. This investigation has uncovered a unique catalytic
stereodiscrimination process controlled only by differences in
the activation entropies.
The primary aim of this study was to extend our newly
developed organocatalytic system to asymmetric 1,4-addi-
tions reactions of nitroolefins.[13] A plausible interaction mode
for the catalytic reactions of nitroolefins with nucleophilic
anions is shown in Scheme 1. In the reactive complex
involving an acyclic guanidine/bisthiourea organocatalyst,
the thiourea moiety can interact with the nitro group in the
Scheme 1. The structures of 1 and 2, and working model for 1,4-
additions with nitroolefins.
acceptor and ionic interactions with the guanidinium cation
can orient a nucleophilic anion.[14] We envisaged that a long
chiral spacer between the two centers in the catalyst would be
required for the promotion of the 1,4-addition reactions that
take advantage of these synergistic proximity effects.
In the current study, we initially selected catalytic
asymmetric Friedel–Crafts (FC) reactions[15,16] of phenol
derivatives.[17–19] Although a variety of electron-rich aromatic
compounds such as indoles, pyrroles, and furans have been
successfully utilized as nucleophiles in 1,4-addition process-
es,[15,16] asymmetric reactions of phenol derivatives have been
rarely studied. The difficulty in employing phenol derivatives
in these processes could be a result of two intrinsic factors that
are related to the fact that phenoxide anions generated in situ
1) often promote ligand exchange with metal catalysts,[17] and
2) can participate in reactions that take place with low levels
of chemo- and regioselectivity. In 2007, Chen and co-workers
developed the first 1,4-type of FC reaction of naphthols with
nitroolefins that utilize cinchona-based thiourea catalysts.
These processes give ortho-selective FC products with 85–
95% ee.[18a] However, the undesired dimeric furans that are
formed in these reactions cannot be easily separated from the
target chiral phenols. Following this early study, most catalytic
reactions of phenols were designed to prepare pyrans[18b,c] and
chromanes[18d] through C-alkylation/O-cyclization cascade
processes. Thus, to broaden the utility of this process in the
preparation of chiral phenols, alternative approaches have
been explored to repress the inherent cascade pathway.[18e]
To evaluate the catalytic activities of newly designed C3-
tethered guanidine/bisthiourea catalysts,[20] initial studies
were conducted using sesamol (3a) and nitroalkene 4a
(1.0 equiv) as substrates.[18e] As the results displayed in
Table 1 show, 2 effectively promotes nucleophilic addition at
the C6 position of 3a to selectively afford the corresponding
[*] Dr. Y. Sohtome, B. Shin, N. Horitsugi, R. Takagi,
Prof. Dr. K. Nagasawa
Department of Biotechnology and Life Science
Faculty of Technology
Tokyo University of Agriculture and Technology
2-24-16 Naka-cho, Koganei, Tokyo 184-8588 (Japan)
Fax: (+81)42-388-7295
E-mail: sohtomey@cc.tuat.ac.jp
knaga@cc.tuat.ac.jp
Prof. Dr. K. Noguchi
Instrumentation Analysis Center
Tokyo University of Agriculture and Technology
2-24-16 Nakamachi, Koganei, Tokyo 184-8588 (Japan)
[**] We thank the Grant-in-Aid for encouragements for Young Scientist
(B) and The Uehara Memorial foundation. B.S. is grateful to a
Sasagawa Scientific Research Grant.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003172.
Angew. Chem. Int. Ed. 2010, 49, 7299 –7303
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7299

Communications
Table 1: Catalyst screening and optimization studies.
Table 2: Asymmetric FC reaction with various phenol derivatives 3 and
nitroolefins 4 catalyzed by 2i.
Entry
3
4: R
Product 5
t [h] Yield ee
[%][a] [%][b]
4b:
4Cl-C6H4
Entry Cat. R1
R2 R3 T [8C] t [h] Yield [%][a] ee [%][b] Config[c]
1
2
3a
5ab
5ac
12
12
99
91
90
87
3a 4c:
4-MeOC6H4
3a 4d:
2-naphthyl
3a 4e:
2-thienyl
3a 4 f: 2-furyl
1
2a C18H37
H
H
H
Me ꢀ10 12 55
Bn ꢀ10 12 69
iPr ꢀ10 12 66
Me ꢀ10 12 35
Bn ꢀ10 12 62
iPr ꢀ10 12 71
Me ꢀ10 12 88
Bn ꢀ10 12 88
iPr ꢀ10 12 88
iBu ꢀ10 12 82
22
22
8
R
R
R
R
R
R
S
S
S
S
S
S
S
R
2
3
4
5
6
7
8
2b C18H37
2c C18H37
2d -(CH2)4-
2e -(CH2)4-
2 f -(CH2)4-
2g -(CH2)5-
2h -(CH2)5-
3
4
5
5ad
5ae
12
9
99
98
99
94
90
88
21
15
2
5af
5ag
12
48
43
41
78
50
80
85
91
34
6[c,d] 3a 4g:
84[e] 91
66[e] 90
88[e] 89
c-C6H11-
3a 4h:
CH3(CH2)5-
3a 4i:
Ph(CH2)2-
9
2i
2j
2i
2i
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
-(CH2)5-
7[f]
8[f]
5ah
5ai
24
24
10
11
12
iPr
iPr
iPr
iPr
0
20
20
20
12 95
2
9
9
96
97
46
13[d] 2i
14[d] 1i
9
10
3b 4a: Ph
3b 4d:
2-naphthyl
3b 4e:
2-thienyl
12[h] 3b 4j:
CH3(CH2)2-
5ba[g]
5bd
12
12
95[e] 88
84
[a] Yield of the isolated product. [b] Determined by HPLC on a chiral
stationary phase. [c] The absolute configuration of 5aa was determined by
using X-ray crystallographic analysis of a derivative. See the Supporting
Information for details. [d] The reaction was carried out in toluene at a
concentration of 0.025m. Bn=benzyl.
84
11
5be[g]
5bj[g]
12
24
99
84
90[e] 93
13[f]
14
3c 4a: Ph
3c 4b:
5ca
24
24
77
78
82
83
FC product 5aa. The results of extensive catalyst develop-
ment studies suggested that both the six-membered ring
containing the guanidine moiety and the a-branched sub-
stituent on the chiral spacer are crucial for the achievement of
high levels of asymmetric induction (Table 1, entries 1–8 vs.
entries 9 and 10). Among the catalysts probed, 2i bearing an
isopropyl moiety on the chiral spacer gave the best results in
terms of both reactivity and enantioselectivity (Table 1,
entry 9; 88% yield with 78% ee). Notably, we observed that
the enantiomeric excess of 5aa increased as the reaction
temperature was increased, thus reaching an ee value of 85%
at 208C (Table 1, entries 11 and 12). Finally, tuning the
solvent concentration led to the optimum processes in which
5aa was produced with 91% ee (Table 1, entry 13). Thus, this
investigation led to the development of a highly atom-
economical protocol[21] for 1,4-type FC reactions of phenols
and nitroalkenes. The importance of the length of the
C3 spacer on 2i is evident from a comparison of reactions
promoted by this catalyst versus its structural variant 1i that
bears a C2 spacer (Table 1, entry 13: 97% yield, 91% ee vs.
entry 14: 46% yield, 34% ee).
5cb[g]
4-ClC6H4
[a] Yield of the isolated product. [b] Determined by HPLC on a chiral
stationary phase. [c] The reaction was carried out in toluene at a
concentration of 0.1m. [d] 1.5 equivalents of 3a was used. [e] Yield based
on 1H NMR spectroscopy. [f] 2.0 equivalents of 3 was used. [g] The
absolute configuration of 5 was determined by comparison of the
[a]D values with those reported earlier.[18a] [h] 10 mol% of 2i was used.
tration (0.1m) was required for good conversions (Table 2,
entry 6). 2-Naphthol (Table 2, entries 9–12) and 1-naphthol
(Table 2, entries 13 and 14) also reacted and gave the
corresponding FC adducts 5 in 77–99% yield with 82–
93% ee.[18a]
Subsequent kinetic analysis based on an Eyring Equation
[see Eq. (1)][22] revealed the effects of differential activation
enthalpies (DDH°SꢀR = DH°SꢀDH°R) and activation entro-
pies (DDS°SꢀR = DS°SꢀDS°
reactions catalyzed by 2i.
)
[23–26] on the enantioselective FC
R
The catalyst 2i developed in the exploratory studies was
applied to reactions of various phenol derivatives 3 and
nitroolefins 4 (Table 2). Nitroolefins having aromatic groups
(Table 2, entries 1–5) as well as aliphatic substituents
(Table 2, entries 6–8) participated in the catalytic process,
and afforded the corresponding Friedel–Crafts products with
87–94% ee. For the less reactive nitroalkene 4g that bears a
bulky aliphatic substituent at the b position, a higher concen-
lnðkS=kRÞ ¼ ꢀDDH°SꢀR=RT þ DDS°SꢀR=R
ð1Þ
First, in accord with Equation (1), plots of natural
logarithms of the relative rates of formation of (S)-5aa and
(R)-5aa, that is, ln(kS/kR) = ln[(100 + % ee)/(100 ꢀ % ee)]
versus the reciprocal of the temperature for each reactant
7300 www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 7299 –7303

Angewandte
Chemie
concentration gave straight lines with good correlation
coefficients (Figure 1).[26] These results document that a
single reaction mechanism of catalysis is followed in the
temperature range at each concentration.[23e]
the entropy-controlled catalytic systems is that they do not
need high levels of temperature control to attain maximum
stereoselectivities. In addition, the entropy term can be tuned
by altering the reaction conditions—an important component
in the design of switchable functions of organocatalysts.[23b]
As the plots in Figure 2 show, the DDH°
and
SꢀR
DDS°SꢀR values for the reaction of 3a with 4a promoted by
2i are reasonably well-fitted to a straight line with a good
Figure 2. Enthalpy–entropy plots for the Friedel–Crafts reaction of 3a
with 4a catalyzed by 2i.
correlation coefficient (R2 = 0.979). A unique feature of the
enthalpy–entropy compensation line is the positive value of
the intercept (DDS°0 = 26.6 Jmolꢀ1 Kꢀ1). These results suggest
that the stereodetermining step in the present process is
associated in part with differences in solvent orientation
about the catalyst.[28] We speculate that a decrease in the
concentrations of substrates in the catalytic enantioselective
FC reaction catalyzed by the C3-tethered guanidine/bis-
thiourea catalyst 2i results in destruction of the structure of
toluene around the catalyst and leads to an increase in the
magnitude of the differential activation entropy in the
stereodetermining process. Further studies designed to
probe the link between thermodynamics and molecular
mechanism are underway.
In summary, the studies described above have resulted in
the development of a new strategy for asymmetric organo-
catalysis that involves the use of conformationally flexible
organocatalysts. The developed chiral C3-linked guanidine/
bisthiourea 2i was found to promote ortho-selective 1,4-type
FC alkylation reactions of phenols with nitroalkenes that take
place with 82–94% ee. The availability of acyclic scaffolds
that can be used as asymmetric organocatalysts may broaden
the concepts involved in catalyst design. Kinetic studies by
using Eyring plots provide evidence that differences in the
activation entropies play a principal role in the stereodiscri-
mination seen in FC reactions catalyzed by 2i. The ability to
attain maximum enantioselectivities over a wide reaction
temperature range leads to operationally simple organo-
catalytic systems that do not require fine-tuning of the
reaction temperature. Further efforts to apply the entropy-
controlled organocatalytic system to other classes of asym-
metric transformations, including enantio-switching, regio-
switching, and organo-cascade processes are ongoing.
Figure 1. Temperature dependence of the enantioselectivity in the 2i-
catalyzed enantioselective FC reaction of 3a with 4a at various
concentrations; 0.025m (circle), 0.05m (cross), 0.1m (square), and
0.2m (triangle). See the Supporting Information for details.
As seen by inspecting the data in Table 3, with the present
catalytic system, differential activation parameters were
found to depend on the concentration of the reaction mixture.
Both the DDH°
and DDS°SꢀR values are reduced as the
SꢀR
reactant concentration is decreased. Cooperative contribu-
tions of the positive values of DDH°SꢀR and DDS°SꢀR (Table 3,
entries 1–3) explain the unusual temperature profile observed
(Table 1, entries 10–12). Specifically, when the concentration
decreases to 0.025m in the FC reaction catalyzed by 2i,
DDH°SꢀR approaches zero, and DDS°SꢀR becomes responsible
for the stereodiscrimination (Table 3, entry 4). These results
contrast with those seen in general organocatalytic systems
that employ conformationally rigid organocatalysts, where
stereoselectivities are dominated by enthalpy differences.[23] It
is important to note that entropy-controlled asymmetric
catalysis has not been reported previously.[27] An advantage of
Table 3: Differential activation parameters for the FC reaction of 3a with
4a catalyzed by 2i at various concentrations of the substrates.
Entry
Concentration [m]
DDH° [kJmolꢀ1
]
DDS° [Jmolꢀ1 Kꢀ1
]
1
2
3
4
0.2
0.1
0.05
0.025
12.6
9.65
7.97
ꢁ0
59.0
53.8
51.1
25.4
Angew. Chem. Int. Ed. 2010, 49, 7299 –7303
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7301

Communications
[12] a) E. L. Eliel, S. H. Wilen, L. M. Mander, Stereochemistry of
Organic Compounds, Wiley, New York, 1994; b) Flory, P. J.
Statistical Mechanics of Chain Molecules, Interscience, New
York, 1969.
Received: May 26, 2010
Revised: July 16, 2010
Published online: September 2, 2010
[13] For reviews on organocatalytic asymmetric 1,4-conjugate addi-
tions, see: a) S. B. Tsogoeva, Eur. J. Org. Chem. 2007, 1701; b) D.
Almasi, D. A. Alonso, C. Nꢃjera, Tetrahedron: Asymmetry 2007,
18, 299; c) J. L. Vicario, D. Badia, L. Carrillo, Synthesis 2007,
2065.
Keywords: entropy · Friedel–Crafts reaction · hydrogen bonds ·
organocatalysis · phenols
.
[14] Discussion about the chemoselectivity of guanidinium cations
and thioureas: a) B. R. Linton, M. S. Goodman, A. D. Hamilton,
Chem. Eur. J. 2000, 6, 2449; b) Y. Sohtome, A. Tanatani, Y.
Hashimoto, K. Nagasawa, Chem. Pharm. Bull. 2004, 52, 477.
[15] a) C. Friedel, J. M. Crafts, Hebd. Seances Acad. Sci. 1877, 84,
1392; b) C. Friedel, J. M. Crafts, Hebd. Seances Acad. Sci. 1877,
84, 1450.
[16] For recent general reviews on catalytic asymmetric FC reactions,
see: a) T. B. Poulsen, K. A. Jørgensen, Chem. Rev. 2008, 108,
2903; b) K. A. Jørgensen, Synthesis 2003, 7, 1117; for recent
reviews on organocatalytic asymmetric FC reactions, see: c) S.-
L. You, Q. Cai, M. Zeng, Chem. Soc. Rev. 2009, 38, 2190; d) V.
Terrasson, R. M. Figueiredo, J. M. Campagne, Eur. J. Org. Chem.
2010, 2635.
[17] For exceptional examples of metal-based Friedel–Crafts reac-
tion of phenol derivatives with a stoichiometric amount of chiral
alkoxyaluminum chloride, see: a) F. Bigi, G. Casiraghi, G.
Casmati, G. Sartori, G. Fava, M. F. Belicchi, J. Org. Chem.
1985, 50, 5018; with chiral zirconium catalyst, see: b) G. Erker,
A. A. van der Zeijden, Angew. Chem. 1990, 102, 543; Angew.
Chem. Int. Ed. Engl. 1990, 29, 512; cooperative system with
metal and chiral phosphoric acid, see; c) J. Lv, X. Li, L. Zhong, S.
Luo, J.-P. Cheng, Org. Lett. 2010, 12, 1096.
[18] For asymmetric organocatalytic 1,4-type Friedel–Crafts alkyla-
tion/cascade reactions of phenol derivatives, see Ref. [17c] as
well as a) T.-Y. Liu, H.-L. Cui, Q. Chai, J. Long, B.-J. Li, Y. Wu,
L.-S. Ding, Y.-C. Chen, Chem. Commun. 2007, 2228; b) X.-S.
Wang, G.-S. Yang, G. Zhao, Tetrahedron: Asymmetry 2008, 19,
709; c) X.-S. Wang, C.-W. Zheng, S.-Li. Zhao, Z. Chai, G. Zhao,
G.-S. Yang, Tetrahedron: Asymmetry 2008, 19, 2699; d) L. Hong,
L. Wang, W. Sun, K. Wong, R. Wang, J. Org. Chem. 2009, 74,
6881; Although the chemo- and regioselective catalytic asym-
metric 1,4-type Friedel–Crafts reaction was recently reported,
the catalyst efficiency (ꢀ408C, 96 h) and the substrate generality
still remain formidable issues; e) H. Zhang, Y.-H. Liao, W.-C.
Yuan, X.-M. Zhang, Eur. J. Org. Chem. 2010, 3215.
[1] a) A. Fersht, Structure and Mechanism in Protein Science: A
Guide to Enzyme Catalysis and Protein Folding, Freeman, New
York, 1999; b) R. B. Silverman, The Organic Chemistry of
Enzyme-Catalyzed Reactions, Academic, San Diego, 2002.
[2] a) G. Jeffrey, W. Saenger, Hydrogen Bonding in Biological
Structures, Springer, Berlin, 1991; b) G. R. Desiraju, T. Steiner,
The Weak Hydrogen Bond in Structural Chemistry and Biology,
Oxford University Press, Oxford, 1999.
[3] For selected reviews, see: a) K. Teilum, J. G. Olsen, B. B.
Kranelund, Cell. Mol. Life Sci. 2009, 66, 2231; b) R. L. Baldwin,
J. Mol. Biol. 2007, 371, 283; c) D. H. Williams, E. Stephens, D. P.
OꢀBrien, M. Zhou, Angew. Chem. 2004, 116, 6760; Angew.
Chem. Int. Ed. 2004, 43, 6596; d) K. N. Houk, A. G. Leach, S. P.
Kim, X. Zhang, Angew. Chem. 2003, 115, 5020; Angew. Chem.
Int. Ed. 2003, 42, 4872.
[4] For selected reviews on asymmtric organocatalysis, see a) A.
Berkessel, H. Grꢁger, Asymmetric Organocatalysis, Wiley-VCH,
Weinheim, 2005; b) Enantioselective Organocatalysis: Reaction
and Experimental Procedures, P. I. Dalko, Wiley, New York,
2007; c) D. W. C. MacMillan, Nature 2008, 455, 304.
[5] For selected recent reviews on asymmetric hydrogen bond donor
catalysis, see: a) P. M. Pihko, Hydrogen Bonding in Organic
Synthesis, Wiley-VCH, Weinheim, 2009; b) Z. Zhang, P. R.
Schreiner, Chem. Soc. Rev. 2009, 38, 1187; c) A. G. Doyle,
E. N. Jacobsen, Chem. Rev. 2007, 107, 5713; d) S. J. Connon,
Chem. Eur. J. 2006, 12, 5418; e) M. S. Taylor, E. N. Jacobsen,
Angew. Chem. 2006, 118, 1550; Angew. Chem. Int. Ed. 2006, 45,
1520.
[6] For selcted recent reviews on guanidine and guanidinium
orgnocatalysts, see: a) T. Ishikawa, Superbases for Organic
Syntheis, Wiley, Hoboken, 2009; b) D. Leow, C.-H. Tan, Chem.
Asian J. 2009, 4, 488; c) T. Ishikawa, T. Kumamoto, Synthesis
2006, 737.
[7] For pioneering work utilizing chiral urea/thiourea catalysts by
Jacobsenꢀs group, see: M. S. Sigman, E. N. Jacobsen, J. Am.
Chem. Soc. 1998, 120, 4901; for other works by Jacobsen and co-
workers, see references [4] and [5].
[8] For Takemotoꢀs original work, see: a) T. Okino, Y. Hoashi, Y.
Takemoto, J. Am. Chem. Soc. 2003, 125, 12672; for other works
by Takemoto and co-workers, see references [4] and [5] as well as
their review b) M. Miyabe, Y. Takemoto, Bull. Chem. Soc. Jpn.
2008, 81, 785.
[9] For our first report of gunidine/bisthiourea organocatalyst, see:
a) Y. Sohtome, Y. Hashimoto, K, Nagasawa, Adv. Synth. Catal.
2005, 347, 1643; for our recent review, see: b) Y. Sohtome, K.
Nagasawa, Synlett 2010, 1.
[19] For other related work, see: a) S. Brandes, M. Bella, A.
Kjærsgaard, K. A. Jørgensen, Angew. Chem. 2006, 118, 1165;
Angew. Chem. Int. Ed. 2006, 45, 1147; b) S. Brandes, B. Niess, M.
Bella, A. Prieto, J. Overgaard, K. A. Jørgensen, Chem. Eur. J.
2006, 12, 6039; c) D. B. Ramachary, G. B. Reddy, R. Mondal,
Tetrahedron Lett. 2007, 48, 7618; d) J.-L. Zhao, L. Liu, C.-L. Gu,
D. Wang, Y.-J. Chen, Tetrahedron Lett. 2008, 49, 1476.
[20] See the Supporting Information for syntheses of 2.
[21] B. M. Trost, Science 1991, 254, 1471.
[22] H. Eyring, J. Chem. Phys. 1935, 3, 107.
[23] For selected reviews concerning on the temperature dependence
of asymmetric transformations, see: a) G. A. Hembury, V. V.
Borovkov, Y. Inoue, Chem. Rev. 2008, 108, 1; b) Y. Inoue, N.
Sugahara, T. Wada, Pure Appl. Chem. 2001, 73, 475; c) D. Heller,
H. Buschmann, Top. Catal. 1998, 5, 159; d) Y. Inoue, Chem. Rev.
1992, 92, 741; e) H. Buschmann, H.-D. Scharf, N. Hoffmann, P.
Esser, Angew. Chem. 1991, 103, 480; Angew. Chem. Int. Ed.
Engl. 1991, 30, 477.
[10] For example, Lovick and Michael reported that the tethered
bisguanidine catalysts in the catalytic nitro-Mannich-type reac-
tion displayed sharply decreased enantioselectivites as the
length of tether was increased: H. M. Lovick, F. E. Michael,
Tetrahedron Lett. 2009, 50, 1016.
[11] After our first report described in Ref. [9a] was published, two
examples of highly enantioselective organocatalysis (> 90% ee)
by utilizing conformationally flexible catalysts have been
reported: a) J. M. Andꢂs, R. Manzano, R. Pedrosa, Chem. Eur.
J. 2008, 14, 5116; b) X. Han, J. Kwiatkowski, X. Feng, K.-W.
Huang, Y. Lu, Angew. Chem. 2009, 121, 7740; Angew. Chem. Int.
Ed. 2009, 48, 7604.
[24] For Inoueꢀs original work, see; a) Y. Inoue, T. Yokoyama, N.
Yamasaki, A. Tai, Nature 1989, 341, 225.
[25] For
a
discussion about differential activation parameters
(DDH°
and DDS°SꢀR) in enantioselective catalysis, see; a) I.
SꢀR
7302
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 7299 –7303

Angewandte
Chemie
Tꢄth, I. Guo, B. E. Hanson, Organometallics 1993, 12, 848; b) J.
Otera, K. Sakamoto, T. Tsukamoto, A. Orita, Tetrahedron Lett.
1998, 39, 3201; c) T. Nishida, A. Miyafuji, N. Y. Ito, T. Katsuki,
Tetrahedron Lett. 2000, 41, 7053; d) D. Enders, E. C. Ullrich,
Tetrahedron: Asymmetry 2000, 11, 3861; e) R. R. Knowles, S.
Lin, E. N. Jacobsen, J. Am. Chem. Soc. 2010, 132, 5030.
[27] For an example of an entropy-controlled supramolecular com-
plexation, see; a) M. V. Rekharsky, T. Mori, C. Yang, Y. H. Ko,
N. Selvapalam, H. Kim, D. Sobransingh, A. E. Kaifer, S. Liu, L.
Isaacs, W. Chen, S. Moghaddam, M. K. Gilson, K. Kim, Y. Inoue,
Proc. Natl. Acad. Sci. USA 2007, 104, 20737; for an entropy-
controlled micellization, see; b) S. K. Mehta, K. K. Bhasin, R.
Chauhan, S. Dham, Colloids Surf. A 2005, 255, 153.
[26] See the Supporting Information for details.
[28] Y. Inoue, T. Hakushi, J. Chem. Soc. Perkin Trans. 2 1985, 935.
Angew. Chem. Int. Ed. 2010, 49, 7299 –7303
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7303